Is it possible to simply re-tap the drain plug hole to a slightly larger size on the aluminum oil pan on my 2006 4.2? Or, am I gonna have to replace the pan since the threads are on their last go-round on the pan with the current plug.

 

There is a solution to this problem which I used to solve mine on my 2005 Escape with the aluminum sump pan. There was an oversize self-tapping bolt already in it when I bought it which leaked. There was no extra remedy after this to be found at any auto parts shop. This is what I used successfully:
http://ecoplugsystem.com/

Watch the videos. There is one for DAMAGED threads (12mm hole in my Escape which the 12mm plug does fit) and one for UNDAMAGED threads in ALUMINUM sump pans. If you have a steel sump pan, they have an unthreaded magnetic housing for that, as well.

I liked it so much that I bought the 12mm one for UNDAMAGED threads in my ALUMINUM sump pan in my 2002 F-150 with the 4.2L V6. You can call this website directly for advice or extra info. You can also buy these products on Amazon. I bought mine directly from the website store and got them within 3 days.

The tiny drain hole takes a little longer for all of the oil to drain but it is worth it in ease of use. Just remove your vinyl condom (I mean "cover") and pull the plug with standard pliers. As long as you hold onto the plug, it won't drop into your drain pan and you won't have fish around for it. Be sure to replace the vinyl cover when done to keep any debris away from the housing -- this keeps the seal between the magnetic plug and its housing clean.

You can even order a permanent plastic tag to hang near the drain plug in case someone else changes your oil -- you don't want them to unscrew the housing.

 

What member boomercarguy stated is a great way to fix the threads, but replacing the pan is easy as well.
I just recently fixed an oil pan leak on my 07 F150 with the 4.2 V6. I didn't even have to jack the engine up to remove the pan, or take any cross members out. While I had the trans. out I went ahead and replaced the RMS as well. Good luck with whichever route you go.

 

That's good to know about the ease of changing the oil pan on the 4.2L V6 engine. Unfortunately, my problem with the threads was on my 2005 Escape drain pan and I would have required a second mortgage and many hours of a mechanic's time to change it out.
I agree with changing the Rear Main Seal while the having the transmission out. It looks like this will be standard procedure when my slave cylinder dies because it is inside the bell housing on my manual 5-speed. I must have missed something - why was your transmission out?

 

I originally thought it was my rear main seal leaking. The leak was coming from between the engine and trans.
When you look at the pic it seems like the leak was coming from the RMS. That's the new seal installed. You can see the oil seeping around the oil pan gasket from end to end.
When the pan was removed, there was NO silicone anywhere on the gasket! I can't believe my seal didn't leak in the 138k miles on the engine! It was leaking from about 100K miles, but got so bad I finally had to just fix it.