Resident Evil 6 might have a few problems, but there's no denying that Capcom has served up a ton of content for players to sort through. Four campaigns, Mercenaries mode, the new Agent Hunt, and the usual assortment of progression-based unlocks designed to gradually reward players for repeat runthroughs.
Read on and be educated...
Taking The Pain Out Of Campaign
If you're new to Resident Evil, the first thing you should know: don't be afraid of the "Amateur" difficulty setting. The rewards are dialed down alongside the level of challenge, sure, but RE6 has a tendency to be a little user-unfriendly at times. It isn't great about communicating what needs to be done in certain situations, particularly during boss fights, and facing a lighter challenge during your initial runthrough can be incredibly helpful.
Along those same lines, experiment with the way you tackle every situation since the game loves to throw every situation at you. One moment you're guiding a snowmobile down a mountain. The next you're sneaking past patrolling insects/zombie/monster-things in a stealth sequence. It can be a little jarring, and threatens to eventually veer off into frustrating territory.
So just relax. Embrace the Game Over screen. RE6 might be bad about telling you what needs to be done, but that old saying "hindsight is 20/20" rings true. You'll often see what you were doing wrong as soon as the You Are Dead screen appears. Take comfort in that and push forward.
Managing Your Resources
The inventory management system has been redesigned somewhat for RE6, but the fundamentals remain the same. You've only got so much space to pack your crap into. Firearms don't use any space in your inventory, but ammo and consumables do. Prioritize defense over offense. If you're stuck between hanging onto a red plant -- which combines with a green to give you six healing pills -- and creating a new ammo stack, stick with the plant. You can almost always run from RE6's monsters, but you can't run when you're dead on the floor.
Also new: green plants take up space in your inventory, but you can also send them to your pill case. Not only does this give you easy, immediate access to healing with a press of the RB (on an Xbox 360 controller), it also frees up additional space in your inventory. Note as well that this doesn't work in reverse. If you find a red plant after sending a single green plant to your pill case, then you'll have to wait until you can find another green to make use of the red.
Dodge, Duck, Dip, Dive, and Dodge
The stamina bar is yet another new feature in Resident Evil 6. You can't simply melee B.O.W.s endlessly anymore, as a fully drained meter renders your powerful close-up attacks ineffective. Stamina is also consumed when you use the new Quick Shot command (LT + RT) to pop off a few rounds at the closest enemy, either stunning them or taking them down entirely.
Your characters are also much more nimble in general. Press A (Xbox 360 controller) along with a direction on the left analog stick while you're aiming down the sights, and you'll dive in that direction. Keep the stick held down and your character will spring back up and keep running, but you can also let go to take aim at nearby enemies from a prone position. As helpful as it is to dive away from an incoming enemy and fire off a headshot from the ground, the badass factor is what should inspire you to do it.
You've also got a set of unlockable skills to juggle. There's no shop to visit in RE6 and no individual weapon upgrades. Instead, you collect skill points throughout the campaigns that can then be spent on a wide range of skills, anything from boosted firearm/melee damage to increased item drops to upping the frequency of downed enemies leaving behind one particular type of ammo.
Skills are assigned in groups of three, meaning you can only have three equipped for use at any one time. These three-packs are set up in the game's menus, with eight different custom slots unlocking once you've completed a single campaign. You set up these slots outside of the game, but you can switch from one slot to another at any time while you play via the game's cellphone-like interface (accesible via the Back/Select button).
"Increased item drops" is probably the most useful skill you can buy early on. Whatever else you might want to purchase, that should be your first choice. Resources are limited in any Resident Evil game, so anything that gives you access to additional resources is well worth your skill point investment. "Field Medic" is also recommended when you're playing solo, since it gives you back a little health when you're rescued from a downed state.
Eventually you'll advance far enough to fill out multiple custom skill sets. That's where the depth of this feature really comes into play. You can only set up your sets outside the game, but you can switch between the different sets at any time as you play. There's a lot of flexibility with the three-skill-per-set limitation, meaning you can easily have different setups to suit a variety of situations.