Played Rifts, D&D 4.0, D&D 3.5, Pathfinder, Star Wars D20, Serenity, and Spycraft.
RIFTS: Expansive multiverse combining a very dangerous world with science fiction and magic. Good for heavily story-based games. I have heard, however, that the Palladium rpg books (of which RIFTS is a part) is constructed using the "Wouldn't it be cool if..." method, and their materials aren't playtested; which basically means if you have a half-decent power gamer they'll break the system in a flash if the GM doesn't limit access to resources.
D&D 4.0: Boring, in my opinion. Eliminated way too much from D&D 3.5, heavily combat focused and reduced the game mechanics too much. In this respect, all of the classes are well balanced, but I'm rather fond of specialization. It's a highly customizable board game, in my mind. The problem in that being if I wanted to play that way, my group and I would just break out Descent and actually play a light-roleplaying combat-based board game.
D&D 3.5: More complicated that D&D 4.0, in some ways off-putingly so. Much more stuff to do outside of combat, but combat is also more complicated and experience-worthy encounters can be more difficult to survive. Problem lies in the errata. 3.5 books aren't published anymore, and if you only have the core resources, you don't have a lot of options. 3.5 published the core "rule" books, and then released book after book of how you're allowed to break those rules. Highly imbalanced system between magic users and non-magic users. For low level characters, the physical characters get their powers right off the gate while the magicians are rather puny and weak. The problem is that physical characters have a very difficult and slow time increasing their physical prowess past that base point without magical augmentation. Meanwhile, magicians start warping reality to their will after level 7 or so.
Pathfinder: As others have said, and as it is popularly marketed, Pathfinder is D&D 3.75. It incorporates some of the streamlining that went into D&D 4.0 without the obsession with balanced combat focus. Suffers from similar problems as D&D 3.5, but heroes tend to find it a little easier to be heroic. I feel it's more player friendly than D&D.
Star Wars D20: Played a continuous campaign of this for almost a year. Loved it. Pretty standard D20 system. Breakability in any technology heavy campaign, however, comes from technology. Your hackers and technomancers are fond of breaking limitations, which requires a heavy security or authority presence (e.g. the Empire, Republic Military, etc.) to keep them checked. Some complaints with the force-power system. System used feats to unlock force categories (force sensitive, sense, control, alter) while skill points were used to increase your ability to use specific actions like force push, heal, lighting, etc. Would have preferred the force categories (sense, control, alter) to have been the skill point system with feats as groups of actions you could perform, which is, IIRC how the D6 system did it.
Serenity RPG: Another standard D20 system. Main change from Star Wars was the huge technology disparity of the core and rim worlds. Also, purchasing system seemed weird. Alternatively there's a D6 system version. Never have played a D6 version, as they tend to be less popular for whatever reason, so I can't really compare and contrast the two.
Spycraft: Most recent and quite possibly my favorite system I've played so far. Very "cinematic" game play style. The PC's are the heroes plus they are largely expected to win and to look completely bad-ass while doing it. NPC's are generated very differently from the PC creation, allows for varying challenges that PC's can't replicated. Turn-based combat is much more free. Floating initiative system means that you can take different actions to change your order in combat. You have two "half actions" with which you can do any combination of whatever. Where as D&D says you have a "standard">"move">"minor" and you can trade down, but not up, in Spycraft "standard" and "movement" are considered equal. So straight from level one, if you want to not move and spend both your half actions to take two attacks, you can do so with no penalty. "Dramatic conflict" has rules for chase sequences, infiltrations, seduction, brainwashing, interrogation, for those situations where you'd rather play out important moments instead of making just a single die roll to determine if you succeed or fail. Same company also has a Fantasycraft system for your sword-and-sorcery pleasure.
