This is something I've been (and still am) tremendously bothered with, and have sinked a considerable amount of time to find something that both works as I'd like it to, and not interfere with the myriad of shortcuts already existing in OS X.
I was pretty partial to using the cmd+alt+ctrl+some key combo for a long time, and it works pretty well across the board. But, if you want something almost bulletproof, and seek to increase your geek cred all at one fell swoop, take a look at this blog post by Brett Terpstra, the guy behind nvAlt, among other things. It walks you through replacing your Caps Lock key with the combo cmd+alt+ctrl+shift, so you can do a 5-key combo (Caps Lock+some key) with 2 keys, which is awesome. This method gives you a whole keyboard worth of shortcuts not used by any app.
PS: Look at the comment section of the blog post to disable the esc functionality.