Probably trying to run for a group that decided they didn't want to do anything. This was a GURPS game although the system didn't matter. We were swapping off who was running and as far as I could tell, the other players wanted me to run an "adventure" where they went around shopping and took a vacation where nothing bad happened. Right there I should have stopped and asked if everyone wanted a break, maybe watch a movie or something. Instead I kept at it and eventually found something that motivated them. Unfortunately it didn't motivate their characters to do something, it motivated the players to rant at me. Yes I eventually railroaded them (local nobility stole their airship) but I didn't feel bad doing it because this was after an hour or two of trying to tease them into various different adventures, plot hooks, and even just outright asking them what they wanted failed. And frankly they'd been the ones who asked me to run in the first place.
Got a couple more that ran into the PC invincibility theorem where players just expect to go toe to toe with anything you throw at them and win, largely by hiding behind numbers on a character sheet even in games and game systems where that's discouraged.
Two mistakes that ended up being fun in the end:
1. Amber Diceless RPG - If you're not familiar with Amber, suffice to say it's a setting where the players are among the few who can walk between worlds. And they're all pretty much as tough as your average action movie star or Greek hero. With a moment's thought you can see how just about any character can easily upset your average adventure. But that wasn't my mistake, that's just what's built into the system and setting. I could handle that. My mistake was letting someone have a bag that let them gate in things from another world. It was a pretty cheap item (Amber is a points system). The issue was the player, who was new. He decided to go megalomaniac on us and pull troops in to assault the castle where all of the PCs lived along with other people who could walk between worlds. I should have said no but I thought I'd be nice and let him run with his idea. In the end, his guys had overrun the place but were being pushed back until he eventually surrendered. Everyone had a lot of fun and just kind of ran with it. Among other things watching the thin, pale sovereign walk down the halls in a bathrobe carving up gorilla space marines with a sword while ranting at the top of his lungs about people making a mess in his damn castle amused everyone.
2. Earthdawn (original FASA system) - My group was two PCs who couldn't have been more different. One had very little health and mediocre damage but could hit anything and was very difficult to hit in return. The other was more of a brick. So I made a slug monster Horror with a big maw and a tiny but accurate pea shooter type appendage to challenge each of them. I thought I made it tough enough but it was the big bad for that session and... it would have died in like 2-3 rounds. Fast rounds. So on the fly I described an odd glow and figured the thing had more health. And then they killed it twice over. And then a third time... and I finally let it die. Afterward they ended up using part of it to make an item and the players thought it was awesome that one of their first adventures had contained an epic battle.
