assume you're talking about DnD. both seem fun, but 4e is a lot more tactics-based in terms of squares, distance, bursts, etc. its simpler to play if you're a stickler for rules, but some of the control's taken from you in terms of trying to be creative in combat (only having played them; more of a homebrewer myself)
but if you're talking about 4.0 of Candies and Zombies....
first of all, humans are overpowered, and everyone wants to play one. doesn't help that they dropped the 3.5 "one human per party" cap
they made having The Lumps status way weaker, which makes playing a lumpy folk way less effective
whywolves are suddenly contagious, so they're not only hard as shit to kill, but one bite and you're one of them. don't remember that in the old lore...
they also make the setting a lot more grimdark. the whole post-apocalypse factor was a little background flavor in the earlier versions, and ever since the Lich [King] got popular, they've been trying to make every character, race, and location into a horrible post-Mushroom War mutant, monster, or tragic freak. takes away from the odd but fun world of the old canon.
they weakened vampires a lot by saying they're not all shapeshifters like Marceline and her dad, which makes them more on the level of other races. take that as you like, good or bad
Werewolf Queen is now treated as a deity rather than a uber powerful monster. like she wasn't unbeatable enough
trying too hard to be Gamma World
on the plus side, candy people don't explode when surprised anymore. canon or not, made them a pain to play as with that weakness
i dunno, lot of the balance and more funloving side of 3.5 went away