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It depends on what you're doing with the image. You can't always tile a sprited image for example, which is a nice advantage for base64 encoding. Size wise they're pretty similar once you count gzipping, though you do have more overhead on base64 since each will have its own set of image headers vs just one for the sprite.

The best is a single sprite sheet encoded into the source file (I believe this is what the Cappuccino framework does for some of the images that make up some UI elements).

gzipped base64-encoded data is about the same size as the original data, though. It only requires more processing to be done.

Base64-encoded images can't be cached, either.

... Why not? They'll be cached in the stylesheet or whatever source you're providing them from.

And when you change the stylesheet, you'll invalidate the cache on all your images.