The Title of the 100th Episode will be “Point of No Return” and is scheduled to air on April 15 2010.

Discuss about the spoilers of this episode HERE.

Episode Description – Episode Stills – Episode Trailer – Trailer 02 (Promotional) 
Clip 01 – Clip 02 – Clip 03 – Clip 03 (Extended) – Advanced Reviews – Forum

E!Online Spoiler Chat (04-12-2010)
Carl in Texas: Come on, please tell us something about Supernatural’s 100th episode!
How about telling you it’s so good it’ll make your head spin? No? OK, here are three true—but very vague—teases for you (sorry, but we just can’t bear ruining it for you): One person will die, one person will make a sacrifice and one person will take on a new role.
Source 

The latest TV Guide Magazine issue has Major Spoilers for what’s going to happen in this episode. Click to see the scans bigger and read:

Thanks to ontd_spnparty and cloex-brosluvr for the scan!

Jared Padalecki said in interview to CW Source that both brothers will be tempted in this episode – Dean by Michael and Sam by Lucifer and they are close to give in.
Source

Michael Ausiello reported that this episode will deal with Dean and Michael relationship and will focus on Dean.

Sera Gamble:
Dean will behave in a way you’ve never seen before. So will Sam. So will Castiel. Actually, I’m particularly proud of where we take Sam in this episode. He has a kind of maturity in dealing with Dean that it took us a hundred episodes to earn.
Source

From Catalina Walsh (who went to the 100th Episode Party)

Supernatural 100th episode is about Michael and Dean, but also Lucifer and Sam.

Matt Webb Mitovich, from Fancast.com posted a spoiler about the upcoming Supernatural 100th episode.

We already know that Samantha Smith will return as Mary Winchester in ‘Supernatural’s 100th episode. Can you tell us more about the other characters they are bringing back? – Leticia
Actually, Smith is returning not for the milestone outing, but for the episode airing two weeks prior, on April 1 (no joke). No. 100 will offer longtime fans a couple blasts from the past, but it’d spoil all the fun if I ID’d them for you. Just pay close attention come April 15.

Question: I’ll send you some birthday cake if you give me some Supernatural scoop about the 100th episode. —Annie
Ausiello: In the milestone episode, airing April 15,”a very important character will sacrifice themselves in a suicide mission,” reveals exec producer Sera Gamble. “We definitely kept in mind that this was [an important] episode. We wanted to deliver something with real scope; it’s about the Archangel Michael. Crises will come to a head for Dean and Castiel. And you’ll see characters you never thought you’d see again.” Here’s the pan I want you to use for my cake.

Source

Question: Seems like a lot of crazy rumors are flying around about Supernatural’s big 100th episode — especially that bit about the major death. Please reassure my terrified heart that it won’t be either Castiel or Bobby. What would our boys do without them? —CY
Ausiello: There’s a death, but I wouldn’t exactly call it major.

Question: Can you give us some more Supernatural scoop for the 100th episode please? —Lizzie
Ausiello: Prepare to see Castiel like you’ve never seen him before: royally pissed off.

Source

In the past few days, thanks to an imdb post, some fans are thinking that maybe we will see three of past characters on the 100th Supernatural episode.

Kristin, from E!Online is talking about it in her spoiler chat this week.

Kat in Milton, Wisc.: OK, so this is probably a false rumor, but I’m going to ask about it anyway. The rumor is that we will see Jo, Bela and Ruby all making an appearance in Supernatural’s big 100th episode. If you could confirm this rumor or salt and burn it for us, we would greatly appreciate it.
An inside source tells me there will be “no special people” in Supernatural’s 100th episode. So…crisis averted?

Source

Once again re-meting to that imdb post, Michael Ausiello revealed one of the guests who will be on the Supernatural 100th Episode:

Question: Please tell me it isn’t true. Please tell me Ruby won’t be in the 100th episode of Supernatural! I’ll give you ice cream with sprinkles on top. —Ann
Ausiello: No, Ruby won’t be in the 100th episode. But Zachariah (Kurt Fuller) will. I scream, you scream, gimme this ice cream!

Source