- Story related, cannot be missed -
Bare information: Defeat Hector LeMans and free the denizens of the Eighth Underworld from his nefarious schemes.
Missable Trophy Checklist:
* If you've missed any of these, I'd simply suggest creating a new game to go ahead and claim them.
*** Spoiler - click to reveal ***(End of the Line)
Chase after Glottis and run down the stairs all the way to the bottom. Open up the casket and free Bruno, the poison victim from Year One. Return up the stairs and meet with the Guardian of the temple to learn where everyone is and the situation. He'll give you a letter to read, and then you can go underneath him to enter the train station. Chepito will be here wading around. Talk to him, then chase after him (or attempt to). Leave the temple and go down the first flight of stairs, then head to the right rather than going down the second set of stairs to enter the mechanic's workshop. Talk to the little gremlins about Glottis, then head into the room underneath them once you've exhausted all possible talk topics. Take the mug and put it on the nearby mug tree, which is right next to the toaster and above a drawer full of rags. Take out a rag, go back to the workshop, and dip the rag in the oil drums near the foreground. Return to the break room and use the oily rag on the toaster.
(Rubacava)
Go to the dock and talk to Velasco. Once he leaves, pick up the ship in a bottle, then head to the Blue Casket. Everyone's missing, so go try and get into Olivia's office. As she prepares, go into the kitchen to find a large keg full of gelatin. Use the ship in a bottle on the keg, then depart for the lighthouse. The door will still be unlocked, so go up and reminisce about Lola, then head to Toto's tattoo shop. Open the medicine cabinet on the wall opposite of Toto's bed to get the liquid nitrogen. Now, with everything you need ready, head back to the garage where the Bone Wagon is kept and give the bottle to Glottis. Once he returns, talk to him, then use the liquid nitrogen on the warm gelatin. Walk towards the vehicle and examine the car for Manny to crack a joke about what it is going to soon become. Walk around to the back of the car and disarm the bomb.
(El Marrow)
Pick up the arm from the corpse, then go to the trash and take the photo. On the table near Eva is a radio; use it to be caught off-guard by Salvador. Take the letter you got back from the End of the Line and give it to the bird, then use the photo on the bird to sacrifice it. Leave the hideout and then head to the right, near where Glottis and the Bone Wagon are parked. Look familiar? We can't track down Bowlsley yet, so take the ladder up, then again to reach the surface streets where some extras are standing. Take the coffee pot in the foreground and then climb the ladder behind the actors. Above them, use the coffee pot, then climb back down and put the pot away. Enter the door to the right, then when you come back out, climb the ladder once more. To the lower left of the ladder, you can find a grinder and a snow machine. The grinder itself is handheld, so walk up to it and put the LSA agent's arm in it. Then (this may just be for me) use 
to take the combined bone grinder. Put it away, climb down all three ladders, and return to the side of the Bone Wagon. Take the controls from him and then look at the green sludge on the ground. You can follow it to the next screen, but after that, take out the bone grinder and use it occasionally to expose the Sproutella that Bowlsley spilled. As you near the large, dark opening to the right, grind more and expose more of the budding mixture until Manny remarks about needing some extra light.
(This part caused me some trouble.) Threaten the beast back some, raising the wagon up as well. You should be able to adjust Manny some to where he can jump over to the walkway against the wall. After you successfully do this, run all the way to the end and attempt to go down, only to climb back up. The beast should be looking at you now, its tail underneath the vehicle. Take out the control once more and lower the Bone Wagon, pinning the creature. Now you're free to take care of Bowlsley. Enter the flower shop and try to talk to him, investigate the surroundings, whatever. Notice the taped up bell near the door? Take out your scythe and uncover it. Re-enter and Bowlsley will be completely changed. All that's left for you now is to take care of Hector.
Head up to the casino and go to the game floor. Talk to the guy in the trench coat a bit to learn what he's doing, then talk to Meche some. Throw the blanket over Chowchilla Charlie and then ask for the LSA member to rig the machine. Enter the bathroom to get some new threads, and then go talk to Brennis, who now works security. The answer to his question will be one of the numbers displayed behind Manny (mine was 20, which was repeated twice on the board). When you exit the elevator, do your best to convince Celso and his wife to purchase the Double N tickets, and you will be able to meet with Hector personally.
After some more story scenes, head towards the foreground and the edge of the roof to see how the sign is being supported by a gargoyle. There is a crack within, so use the remaining bone in the bone grinder to fill it up, then pour the Sproutella on it. You will see another video, and when you regain control yet again, take the long walk to the greenhouse. (Some more scenes later...) Take out the liquid nitrogen and use it, curing you of your affliction, then head back to the car. Look inside and talk to Salvador, and once he's done what needs to be done, investigate the briefcase. Take the Double N ticket from the sprout pile, then run behind the greenhouse and use the ticket to uncover Salvador's sprouted body. With the keys to the trunk in hand, go back to the car, open the trunk, and get the loaded Sproutella gun. But Hector is much too big and he has an unfair advantage. Instead, there is a water tank feeding water to the greenhouse. Take out your gun and shoot it a few times to finish the game.