Yup, all depends on what you’re looking for. If you want pure flat-out speed, check out the benchmarking sites out there that have run the tests (or, try them yourself).
If you’re looking for good tools libraries, each of them (Prototype, jQuery, Mootools) allow you to have pretty decent cross-browser access to whatever DOM element, event, or AJAX request you could think of.
I only really have experience using Prototype coupled with script.aculo.us to do most of my JavaScript work and animations, and thus far it has been amazing… though I have heard some really good things about both jQuery and Mootools.