When you first create an account, you choose your realm (i.e. server), with choices like USEast, USWest, Asia, etc. No clue on which one is most populated, but I'd venture a guess that USEast is the more populated one.
Softcore vs. Hardcore: The default is softcore... if you want to play hardcore, you need to check some box or something when you create a character. In hardcore, if you die at any point during the game... be it to a monster or fellow player, your character is gone... kaput. You can no longer play with that character or recover any gear he was wearing. In softcore, if you die, you just respawn in town no worse for the wear.
Closed vs Open: Generally want to stay on closed where most people are. "Open" is really just for experimenting with strange builds and such, because you can play your offline characters on open together with any gear you've "created" through various programs/cheats. Basically, stay on closed (default option).
Ladder vs non: There is a "ladder" that lasts for about six months to a year (or more)... I suppose the general idea is like a ranking system, where people try to level higher than others. There are certain ladder only runewords. Once a ladder is complete (no real telling when), all of your ladder characters become non-ladder characters, and if you want to start a new character on a new ladder, you have to start fresh. I'd guess most people make ladder characters... but not sure on that one.
FWIW I play US East ladder softcore.
