I've run fantasy & sci-fi in both 3e & 4e. Most of the time was spent on the 3e side as we began using some OGL systems (Conan most notably) when 4e was introduced.
In my opinion, 4e is a significant improvement over 3e and is a poster-child for what an edition update should look like: clean-up, removal of broken or troublesome mechanics and replacement with cleaner mechanics -- without breaking what came before. I can pull just about any 3e book off my shelf and either use as-is or quickly tweak to conform with 4e changes.
GURPS Challenges:
The #1 challenge for me were learning that while GURPS can do pretty much everything, it's not recommended to try and implement it all Day 1. However, once learned, it runs at the table as smooth or smoother than any other system I've played.
#2 - Campaign Construction. It's not hard, but it can be time consuming. Esp. if you're not taking a default GURPS campaign (there are few true settings to pick from). It can be incredibly rewarding to have a campaign with mechanics that accurately emulate what you envision. However, with all those damn adult responsibilities (work + family), I rarely had the time. Build-as-you-go is probably the best approach, but since GURPS doesn't have a lot of published adventures, it can increase your GM prep-time at the start. (Again, if you let it. I found myself doing it quite a bit.)
#3 - GURPS fanatics. I really hesitated to list this but if I'm being honest it was a factor. I'm not talking about SJGames staff or GURPS authors or even most of the fan community here. Rather, I'm talking about the GURPS fanatics that feel their view is the one-true-way. I know it's the Internet and jackasses can be found anywhere. However, the incident rate where general advice questions are met with "you're doing it wrong", "GURPS isn't designed with that mindset", "why would you do that", etc. is way too high. I also find that 90% of the posts are mechanics-related, even when a post is about campaign ideas & adventures.
Don't misunderstand, though, GURPS is a fantastic game. It's probably my all-time favorite RPG. The sourcebooks are RPG treasure troves of ideas even if you're not using GURPS for your rules set. The game runs smoothly at the table and does, more often than not, produce the desired results - from the very cinematic to the grim-n-gritty.
I just wish it focused more on GM-aid (although Character Builder is a miracle!) so that much of the trial-and-error doesn't have to occur at the gaming table but SJGames seems to be changing that with Dungeon Fantasy & Action PDFs (thanks Kromm!) and that the elitist quiche-eating GURPSians weren't more vocal than the rank-n-file.