Combat Takes Too Long
On one hand, I like the tactical options that 4e offers. Unfortunately, I've found it very difficult to get even a fairly mundane encounter resolved in much less than an hour of play time. By the time a typical encounter was finished, we'd been out of the "flow" of the game long enough that it would take some time to get back on track.
The amount of time that it takes to play out a combat encounter in 4e (45 min to an hour or more seems to be very typical) coupled with the 4 or 5 encounters that characters are expected to be able to handle in one game day means that it's likely that one game day will extend across multiple play sessions. For those of us that play once every 2 to 3 weeks, that is not very appealing, as people often forget what they were doing, even though it was "earlier that same day" in the game world. Sure, you can run fewer, more challenging encounters to make up for this, but those often tend to take more time to resolve.
Combat used to provide a nice change of pace from slower, methodical exploration -- that's not just nostalgia, as I ran some B/X and AD&D 1e games in the past year and it held true. My experience with 4e is that combat often just kills the pacing of a session. A climactic encounter with some build-up was a blast for the first 20 or even 30 minutes. After that, player interest dropped off quickly.
4e combat length also makes random encounters -- once a major deterrent to taking frequent rests-- problematic. The time investment required to run a 4e encounter is such that any battles which are not important to the story can feel like a waste of time. But I'm tempted to allow the players to rest without incident because otherwise I feel like I'm punishing the players by wasting their time.
Class Bloat
Once you get through the traditional D&D classes, it gets harder to justify the existence of a class. Some of them don't seem to represent mythical or fictional archetypes; some of the PH2 and PH3 classes seemed like they existed to fill out a combination of role and power source, with the story elements added after the fact. Did the avenger and invoker need to be distinct classes, or could they have been alternate builds for the paladin and cleric? The "primal" power source reads as basically the "druid" power source, with the barbarian feeling kind of shoehorned in.
Powers are too Specific
The powers system seems very inflexible to me, as most powers have very precise effects, which in turn leads to the proliferation of different powers. It also makes characters overly specialized. Yes, if you want your "fighter" to be an expert archer, play a Ranger instead, but it's barely worthwhile for anyone other than the Ranger to bother with a bow, as no other classes in the PHB or PHB2 have any powers that work with a bow, and its 1d10 damage is rather insignificant in the context of 4e monster hit points.
The Essentials approach of basic attacks modified by stances was definitely an improvement on this.
Swinging my Sword with Charisma and Visciously Mocking an Ooze
This has been discussed to death. Yes, it can be rationalized, but after a while we got tired of trying to explain some of this stuff. Most of these "dissociated mechanics" can be explained creatively, but it can pull people of the game while we try to figure out a good way to fit it into the narrative.
Too Many Fiddly Bits
Temporary hit points are handed out like candy and are another thing to have to track.
There are too many +1/-1/+2/-2 to hit/damage/AC/defenses until the start/end of your/target's next turn effects. They are common enough that an individual's modifier to these stats can differ by a point or two every single round of combat. It's too much mental effort to track for a relatively trivial bonus.
