It's a pain to find a place to live. Places will have one open house. You'll show up with 20 other people, checkbook in hand, and be expected to make a decision right then and there. It might be something you only go through once, but if you need to move for whatever reason, it's a hassle.
It can be a monoculture. It was neat at first, but there are cities that offer plenty of opportunity in tech without completely dominating the city.
The nightlife is kind of lame. I live in Austin now, and when I want to go out, I feel like I have a lot more options, especially if I want to do more than one thing that night.
There's a ton of neat stuff in the area – it's truly one of the most naturally beautiful areas I've ever been–, but it takes a car to get there and owning a car is a hassle.
I didn't find most people who lived there particular friendly. I also found it difficult to make close friends, maybe because of the transient nature of SF. I'm hesitant to draw a real generalization from this, though. I may have just had a string of bad luck, but that was my experience.
The weather sucks. A lot of people like it, and it was certainly a nice respite from the 100F+ weather I left when I moved, but it sucked after a while.
There really isn't ONE thing that makes SF a terrible city. It's a lot of little things that add up. Maybe those little things won't matter to you or will be overcome by the positives in SF. For some people that's certainly true, but for me, I couldn't wait to get out. I left as soon as my first lease was up.