The main difference is overall size. There are 5 campaigns(4 in L4D)and most chapters are longer. Some of these campaigns take place partially or entirely in the daylight hours instead of night. The crescendo and finale events are also different. You no longer just camp in an area, gun down the horde then run to the escape vehicle, though there are still a couple of those. Most of them require you to trigger the event and then the event will not stop unless the survivors deactivate it with another button/switch. Sometimes the only way to stop the horde is to get into the safe room.
There are also many more weapons this time around. All the old weapons are still around but with new shotguns and machine guns, different pistols including a .50 cal magnum. In addition to the new guns there are some special add-ons for them. Laser sights to increase accuracy. Incendiary ammo lights your target on fire when shot and Explosive ammo, which turns your bullets into mini frag grenades. Both special munitions are limited to 1 full magazine(8 shotgun shells, 50 M-16 rounds, etc...) before being depleted. Melee weapons are introduced this time around and can vary from a baseball bat or crowbar up to a chainsaw.
The special infected all look a bit different but still work the same. There are also 3 new special infected, the charger, spitter and jockey. The Witch walks around in the daylight levels making her more dangerous and depending on the level could lead to multiple encounters with the same witch.