After you complete the game for the first time and start up a new character, which quests do YOU feel like you need to do, and which do you feel like you can afford to skip? I'm not talking about what the game requires you to do to advance, but the "side quests" that you can technically get away with skipping.

Personally, I loved "Come Fly Away With Me" in my first playthrough, but upon replaying, I realized it felt kind of repetitive and inessential. I ended up skipping it because I knew where Benny was headed, and was eager to get to the strip. I didn't really care much about Manny Vargas's problems, so I headed on to Boulder City and dealt with the Khans. I suppose I might have been able to skip that too, but for some reason that one feels more essential to the plot to me.

I also feel the need to deal with Nipton, one way or another, even though it's not really story-central...

What about you? What do you feel like you're better off skipping, and what do you feel like you just have to do?

"Come fly with me" is always worth doing as its best source of stealth boys in the game, there is also the spacesuit which combines best rad resist and decent DT and theres the food sanitizers which are at least a bit helpful on hardcoe mode.
I don't do it straight away but come back later to do it. Any quests that lead to good unique weapons/armour or skill books I consider essential.

Food Sanitizers are only used on 'Junk Food' and 'Bubblegum'. So they're better off being sold.

I do every quest possible on every playthrough. I get more enjoyment out of it that way.

Whatever ones I don't get the quest achievement for because I killed the person who started it/is important.

I see the Poweder Gangers side quest as a good way to get stimpaks and good karma +NCR rela's.