1. Make it funny.
This goes without saying, I know, but make sure that your caption ADDS something to the cartoon.
2. Make it as concise as possible.
This is important for writing in general, but when it all comes down to 1-10 words, each one counts. Useless words should be cut, and details not critical for the joke should be violently assaulted.
3. Tell a story.
The funniest jokes suggest something deeper, more controversial, more "real-life" than the innocent drawing on the page. There are many great examples of innocent looking cartoons where the caption takes it to another level. The interplay between those two concepts can also be very funny in itself. Patrick House refers to this as the Theory of Mind approach - More details on this here: http://www.slate.com/id/2192564/
4. Make assumptions that others can GET.
Get out of your head, and imagine reading your caption as someone who isn't "seeing" the animated cartoon playing in your mind. Are you assuming too many levels deep into a story?
5. Try to avoid proper nouns.
For the most number of people to get a joke, it should avoid using proper nouns (names of celebrities, brands, products etc). Remember that not only are we getting more connected as a planet every day, but at the same time people aren't watching the same news we are. You'd think it would have been impossible to find jurors who hadn't heard of the OJ Simpson case during his trial, but they found them. Plenty of them in fact.