The big one in my experience is it doesn't play well at all with JavaScript. Single file to my knowledge (I experimented with it briefly) allows all js to load on page and can then embed loaded media as base64. I think it also has heuristics to embed relevant js as well. It still only gets you 90% of the way there, and I came to the conclusion that unless you are doing web archive type work or need audio / video a composite image works well
