I got killed recently in a 4p offline game that had Ambassador on the board. All the reasons why have been alluded to already, but I really think my critical mistake was not understanding when I needed to shift to buying VPs (because I thought there would be significantly more turns left than there actually ended up being). One of my opponents started buying duchies and I thought, well, he's killing his deck right now. But, of course he won. Also, turns out getting 2 Ambassadors is usually not a great move in 4p.
I play almost exclusively 2p on Isotropic, so I'm not that great at 3p or 4p (I don't have as much experience with how powerful attacks are, I'm not as good at sensing when the transitions to "mid-game" and "end-game" happen, etc.) . I actually don't mind this, though, because when I play offline, it's almost always with more than 2 people. And, the people I play with don't play nearly as much Dominion as I do, so it's sort of nice for me to have a "handicap" so everyone has a good chance to win (and people still want to play with me... :>).