Theres 2 main spots where you have to make decisions that you cant reverse. At some point after reaching vegas, you will be greeted by messengers from the different factions telling you to go talk to them. Completing the missions for one of these factions will block you from going and talking to the other factions - but it only blocks those specific quest lines, not all quests, and not even all the other side quests related to those factions.
Near the very end there is a spot where you will clearly be told by the game that continuing on from there is a point of no return. If you continue the main story line from there you cannot stop until the game is over, and no it doesn't just throw you back into the desert afterward, the game is really over. Just make a save right before that spot so you can go back and play around whenever you want to.
I have found out theres a buttload of quests for the NCR and most of them can be done without pissing off the Legion. You have to go very far up eithers chain before the other gets cut off. In my case it was disabling or killing Mr House. I got a popup with about 4 big legion quests saying "QUEST FAILED!" Thats how I knew I was finished. Was pissed me off was every time I killed a legion member I got another popup saying my reputation with them had fallen. Well no fucking shit morans, we're at war!
Also, you can have allies of the Brotherhood, Great Khans, Boomers, and White Glove society. Most of them are actually quite difficult to get and require you do things in a very specific order. For the khans you have to convince one special khan you need allies and you have to kill his boss at a very specific time in the course of the quest. If you screw it up you risk either war with the khans or at the very least not getting their support when the new guy takes over.
White Gloves: You have to make the special pie yourself, call head waiter, let him take the food from the oven, wait for him to walk away, rush and talk to the son (cuz if you talk to him early he wants to walk around with you and the head waiter can NOT be allowed to spot him), walk up to the serving room, wait for asshole to make speech, pop out with son and show everyone he's still alive.
If everything works out you get the hotel penthouse and support of the Gloves. Also, you get an outfit to give to Veronica and complete her quest.
Cass's quest is complicated too and can be permanently messed up if you dont do specific things.
Brotherhood quests require you to NOT replace the current head of the chapter, cuz the new guy will not ally with other factions, but he does treat the courier well with equipment.