#1 Crisis of the Infinite Earths: 1st appearance Blue Beetle in DCU? I read it noted somewhere but I'm not sure.

#2 X-Force Annual 2: I believe this was the debut of X-Treme. At one point in time he was really popular. I liked his ability.

#3 Alpha Flight (1st series) The Debut of the master of the world.

#4 X-Force (1st series) A crossover event with Spider-Man were they fought Juggernaut and Black Tom Cassidy.

Some of my picks for the first 50-

#32 Promethea - one of the most intricately and innovatively constructed single issues of all-time, as well as the end of the world.
#8 Sandman - introduction of Death.
#11 has to be Deadpool, man. I know it's already been said, but c'mon... the whole series is so nicely encapsulated in that issue.
#25 Captain America. See "Death of..."
#18 Marvel Super-Heroes, first Guardians of the Galaxy
21 Saga of the Swamp Thing, obviously

I would've had much more 10 years ago, but a lot of issue numbers have escaped my memory...

#11 or #12 Watchmen - 11 for the reveal or 12 for being the finale to the best comic series of all time
#5 FF - first Dr Doom!
#33 Walking Dead - Crazy Torture Issue!
#48 Walking Dead - Crazier Issue!
#15 Amazing Fantasy or Marvel Man
#21 GiJoe - its responsible for that horrible nuff said month!
#10 Preacher - that ending had my jaw dropped. I dont know, some issue of Preacher should make the list!
then skip from #50 to #60: Y The Last Man!!

or instead:

#1 Youngblood
#2 Daredevil Target
#3 Ultimate Wolverine vs Hulk
#4 Hulk - first Red vs green hulk! OMG!
#5 Ultimates 3
#6 Ultimate Adventures
#7 Marville - we can become Marvel comic creators, this is going to work out great!
#8-#12 Wolverine Origins
#13 Byrne's Lost Generation - the numbering is backwards!
#14-26 Wolverine Origins
#27-49 Countdown
#50 Tarot - boobies = stories

20. Spidey/MJ wedding (a good choice except for the fact that it never happened, of course)
11. Superman Moore/Gibbons
10. Avengers Annual, first Rogue and pretty cool story to boot
3. Reed/Sue Wedding

Other good contenders for other issues:

44. Teen Titans, first Nightwing
36. Spidey World Trade Center issue?
27. Neil Gaiman Hellblazer issue
26. First Bendis Daredevil
18. Sienciewicz's first New Mutants
12. X-men, first Juggernaut, although I'm personally quite fond of the death of Guardian in Alpha Flight, quite the drama in my 11-year old eyes...

I think the top ten are pretty tough to call because so many characters were introduced in those numbers, it's quite subjective which ones are the most significant. For issue three, one fan's Doc Ock debut may be trumped by another fan's Blob.

Legion of Super-Heroes v3 #38 -- death of Superboy.

11 could be Superman Annual (For the man who has everything)

The higher numbers seem like they'd be more interesting, simply because you move past the origin stories.

FunkyGreen - you propose the first appearance of Omega Red, and then mock someone for their Ultimate Spidey pick? I hope you were being sarcastic.

Nahhhhhhhh....

Actually, I wasn't mocking the pick, just the phrasing of it. 'Reveals himself' made me snicker - not the choice of issue, if anything, that was the issue that made me, and I'm assuming a lot of others, suddenly start paying a bit more attention to the Ultimate line - it was the one that made me decide to start picking up the trades, I'd read the first arc on Marvel.com and thought it was alright, but then I read that one online and realised that the book would be going in it's own direction (whether it stuck to that though is a matter of debate).

The silent issue of G.I. Joe would be a pretty kick ass pick for #21.
Grendel could be #20 or #24. #20 since that was when Wagner first ran with the idea of Grendel being more than just the next person to wear the mask, and #24 since it was the first appearance of my favorite Grendel after Hunter Rose, Eppy Thatcher.

21 - JLA First JLA/JSA team-up

13 could be Ultimate Spider-Man, when he reveals himself to Mary Jane.

Am I the only person who snickered when they read that?

#4 - X-men... first Omega Red.

That's about all I can think of. :\