In The Killing Star Pellegrino postulated the concept of interstellar warfare by means of relativistic kill vehicles -- relatively small objects accelerated to near light speed, which would then strike with the force of nuclear weapons owing to their kinetic energy. Pellegrino believed that defense against RKV's would be impossible, because they would travel too fast to be detected before impact. I have thought about this topic for years, and believe that they could be intercepted, by an equally advanced civilization. Here are some of my reasons and conclusions.
Techniques
First of all, a system-wide civilization doesn't have to concentrate all its sensors on the RKV's target. It can build sensor "spheres," which is to say networks of linked sensors, at various distances from its own star, so that the RKV will be detected long before it has reached the densely-inhabited parts of the star system.
This is a direct analogy to anti-missile tactics here on Earth. If a naval task force had to position all its defense on the primary target of a missile attack (the carrier or other large vessel), missile defense would be difficult to impossible. It doesn't: it spreads out its sensors and weapons to create a zone of defense, and tries to shoot down as many missiles early on in the engagement as possible.
The economics are made more difficult by the need for defense in three dimensions, and more easy by the fact that an advanced civilization can manufacture simple sensor platforms in quantity through von Neumann automation. It would not so much "emplace" the sensor spheres as "grow" them, with the growth monitored by sapients to curb mutational runaways.
Secondly, while detecting RKV's through active means would require a lot of power (you might have to set off periodic "flare" fusion or antimatter bombs to generate a sufficient return), RKV launches would be detectable across near-interstellar distances and a decent-sized RKV would be passively detectable in flight as it ran into atoms of gas and bits of dust. One can also assume that most RKV attacks would be launched in waves rather than stray shots, to increase the chances of at least some RKV's penetrating.
Thirdly, the relativistic effects of high-speed travel are known and predictable. Unless the RKV dodges, one good measurement of its vector (which requires two observations) will tell the defender where it is from that point on. Now, the RKV can dodge, but to dodge it must expel reaction mass, which is an event orders of magnitude easier to detect than the mere presence of the RKV itself.
Admittedly, the rapid calculations involved are beyond the capability of an unaugmented contemporary human mind, possibly beyond the capability of contemporary human computers, but a system-wide civilization would have both better minds and better computers.
Fourthly, the same technologies that enable RKV's enable anti-RKV's -- an anti-RKV might be as simple as a single missile, launched at relativistic speeds to position itself in the path of the RKV, or as complex as a missile which explodes in its path to create a barrier of numerous particles which act as a minefield upon which the attacking RKV runs. Yes, the RKV can dodge, but assuming equivalent technolgies, the anti-RKV can maneuver to compensate. Here, comparative capabilities and intercept geometries become important, making the situation tactically interesting.
Finally, if one already knows where one's enemies' bases are, one need not watch the entire sphere with equal attentiveness: one can focus much of one's attentiveness on the direction from which the enemy must come. This leads of course to the possibility of flanking maneuvers, feints, and the like -- and makes things strategically interesting.
In conclusion, RKV attacks would not be 100% effective, and so the doctrine "strike first to avoid future danger," espoused by Pellegrino's genocidal Alien Space Bats, would not be a rational one, and certainly not one which could be expected to be universal. A first strike might be stopped by a superior defense, especially if it was against a more advanced race, in which case one would have just bitten off more than one could chew. Diplomacy would be useful, in interstellar as in interplanetary or terrestrial warfare.
On the other hand, Pellegrino was certainly right when he pointed out that, especially at our current level of technology, squawking our existence openly to the Universe is not such a bright idea. Note that we could not today use any of the defensive methods I've outlined here: we are far from being a system-wide civilization.
Terminology
Here are some terms I use to discuss RKV warfare:
Relativistic Kill Vehicle (RKV)
What we're trying to stop. An object with mass accelerated to a significant fraction of lightspeed, such that it strikes with kinetic energy sufficient to convert a significant portion of its mass to energy. RKV's are launched from RKV launchers, but may carry some energy and reaction mass onboard to allow for some maneuver after launch -- the better to counter dodging and evade A-RKV's.
RKV Launcher
The weapon which launches an RKV. The energy-economics work much better if the RKV need not carry most of the energy needed to accelerate itself onboard. RKV launches are probably detectable at interstellar distances, so it aids stealth to launch the RKV from a greater distance (though it reduces strategic flexibility for the obvious reasons).
Sensor Platform, and Sensor Sphere
The most basic object, this is an automated station with some sort of radar and ladar capabilities. Very large numbers of them are replicated and positioned in concentric spheres, mostly in the extreme outer system being defended.
A-RKV Missile
The best way of stopping an RKV at long range. It consists of a (usually very maneuverable) RKV which attempts to intercept and collide with the attacking RKV, in order to prematurely detonate it.
A-RKV Beam
The best way of stopping an RKV at shorter ranges. It consists of a powerful energy beam, which attempts to destroy the RKV by pumping thermal and/or kinetic energy into it.
Danger Cloud
When an RKV is detonated it does not cease to exist. Instead, the dispersed remnants become a rapidly expanding sphere of plasma still travelling at relativistic velocities. If the danger cloud is generated too close to the target ("too close" is based on the passive defenses, such as armor and electromagnetic shielding, of the target) then the RKV may still succeed in destroying the target despite having been intercepted. Past a certain point for any particular target, the cloud disperses to a mere nuisance.
Dodging
An object which can move under its own power can avoid an RKV which has no more ability to maneuver by simply getting out of its way. If the RKV is detected early enough (at interstellar distances), such objects might include planets, as a system-wide civilization has a lot of power to play around with! Such objects will certainly include spacecraft, and perhaps many space and asteroid habs.
Shielding
It is possible to generate electromagnetic shields, and use wide-aperture beam weapons to ionize any matter approaching the shields. This is a useful last-ditch defense against Danger Clouds, but not very useful against intact RKV's because an intact RKV is dense and fast enough to smash right through the shield with very little dispersal.
Sheltering
If your planet is going to be hit and you can't intercept or dodge the hit, one defense is to "shelter" -- to put everything vulnerable on the planetary surface into deep subterranean shelters which protect it against anything but fairly direct hits. This implies interstellar detection of the RKV's, and it also implies that the planet isn't being hit by enough total energy to turn the crust into molten slag, so it is a limited sort of defense. "Everything," by the way, includes the planetary atmosphere, hydrosphere, and ecosphere, so the prerequisite civil defense engineering is non-trivial :)
System Defense Station
An anti-RKV armed space station designed to protect a system from RKV attack. It is not very mobile and hence can only cover a limited set of angles of space. These tend to be heavily built along likely paths of attack, while System Defense Cruisers deal with the threat of RKV's from Launch Cruisers. System Defense Stations tend to be heavily armored and shielded, because knocking out such Stations is an obvious first-wave objective to permit follow-on waves to penetrate the enemy system.
RKV Launch Cruiser
Also called an "RKV Boomer," by analogy with an SSBN. This is a starship designed to carry RKV's and bombard a system from unexpected angles, thus circumventing stationary defenses.
System Defense Cruiser
A spaceship designed to carry anti-RKV weapons. System defense cruisers are useful in providing a flexible response to an enemy using RKV Attack Cruisers, and hence trying to flank stationary defenses.
Stellar Cannon
A very powerful energy beam, often powered by the rechannelled total output of the system's star, which can be used either to attack across near interstellar distances (such an attack, much of which travels at lightspeed, is hard to defend against), or to defend against RKV's (the beam is deliberately dispersed into a wide aperture and destroys all the RKV's in the cone of its path). There are obvious engineering and operational difficulties which limit its effectiveness.
Stellar Shield
A very powerful electromagnetic shield, probably incorporating sandcasting on a massive scale, which is one of the only general defenses against stellar cannons. Similar engineering and operational difficulties limit its use.