These are all the ones I've used even in a minor way:
ESPN - it's just not a simplistic interface that you can easily manage. I use to have a league or 2 on there and left purely for that reason. They try to make it way more complicated than it needs to be IMO. Never got use to it so I stopped trying and kept most of my leagues on Yahoo for it's simplicity.
Yahoo - easiest by far. Tools, Scoring, ease of access, stattracking all are aces. The only thing is if you want it to be a keeper league then those settings are hard (at least to me) to figure out.
MFL - if you're doing dynasty this is your best bet probably but it costs money. It's straight forward in its format, but it's a little hard to find the information you want to actually find. It takes some digging. Not the easiest to maneuver but all the features are there.
Bonus sites:
Sleeperbot - I just opened a league on here and it seems like it's amazing at first glance. The setup was extremely easy. Scoring is straight forward, with plenty of options to customize. Ease of use for us young folks is amazing (app and mobile site), plus it has almost a built in message board you can participate it with news updates easy to find. That's as far as I've gotten in terms of use, but I have a rookie draft on there this week so I'll report back.
FleaFlicker - Is this site still around? I tried to migrate one of my Yahoo leagues over to this but the owners in my league were hesitant. Understandable. But the features on here seem like the best. TONS of customization options if you have a very unique league.