IV is pretty standalone so far.
You could easily skip the first game, but you absolutely have to play II - Brotherhood - Revelations as they tell one continuing and excellent story. The present day half of that story climaxes in III, but the main past section of III is a new unrelated character.
I would highly recommend skipping the first game. It's visually gorgeous but you literally perform the same five tasks over and over for the entire game, and the story isn't nearly as interesting as the later games. You could read the wikipedia synopsis of the story and miss very little if you start with II.
I: Desmond (present), Altair (past)
II: Desmond (present), Ezio (past)
Brotherhood: : Desmond (present), Ezio (past)
Revelations: : Desmond (present), Ezio (past), Altair (past)
III: : Desmond (present), Connor (past)
IV: new guy (present), Edward (past)