I'm leaving this as a sticky post, so I'll add to it over time and cross out ones that have been answered.
Both Jared and Jensen
Knowing what they know now, if they each had a chance to reach back through time to when they first started on the show to give themselves one piece of advice, what would it be?
How many episodes before actually getting the script for Death's Door did they learn Bobby was going to die? How did that knowledge affect their performances in the episodes leading up to the event?
What things have they learned from various people on Supernatural's crew - folk like Serge Ladouceur and Jerry Wanek - that have made them better at their craft or that they will carry with them through the rest of their careers?
What have they learned from working with some of the wonderful directors on Supernatural - especially Kim Manners, Phil Sgriccia, Guy Norman Bee, and Bob Singer - that has made them better at their craft or made them look at their performances in a different way?
Thinking about the directors they've liked working with the most: what characteristics - beyond just being prepared! - set them apart?
How would they each describe - no more than five words each! - the following people: Kim Manners, Phil Sgriccia, Guy Bee, and Bob Singer?
What have they each learned about their acting craft and their characters this season that they didn't know before?
Thinking about each season of Supernatural, what acting or life lessons did they take from each season? Which season was personally the most life-changing for them (meaning, for Jared or Jensen, not Sam or Dean!)?
Which episode performance so far this season by the OTHER actor did they each think was best, and why? (So, have Jared pick what he thinks was Jensen's best, and Jensen pick what he thinks was Jared's best.) If that "best" is something we haven't seen yet and can't be spoiled, provide the second-best with a promise of more to come!
What is the most challenging part of playing a dual role that shares a scene (eg, Sam meeting Soulless Sam and Hell Sam in The Man Who Knew Too Much; Dean meeting his future self in The End and his doppelganger in Dream A Little Dream Of Me)? What is its greatest reward?
In The Mentalists, when Sam first encountered Dean in the diner, I got the distinct impression that Sam originally thought Dean might be a hallucination; it seemed that Sam tried to ignore Dean until the waiter spoke to him, confirming he was real. Was that your intent? (It was subtle and GREAT!)
How much were you able to be involved in the editing and post-production on the episodes you directed, given that you were shooting other episodes as soon as you finished shooting the ones you directed? Were there things about the final cuts that surprised you?
I'll add to this later (NEVER run out of questions, and need to set them up for additional folk beyond Jared and Jensen!), but I wanted to put it out there. Hope it proves useful! If you've got good questions to add that you'd like to make available to others, leave them in the comments, and I'll move them up into the body of the main post to make them easy to find.