Let It Go!
What should a writer do with his or her manuscript, which has been (repeatedly) rejected by agents and publishers?
One option is to self-publish. And as hard as it may be to do, the second best option may be to, as Colin Broderick advised, "LET IT GO!" And move on to writing the next book. Broderick advised:
My advice is just write: write, write, write...but just as important: know when to let go. You must let go in order to move forward. Again and again I see young writers I admire getting stuck on one book. They try to get it published and nobody wants it and they go back and tweak it again and again for years without getting into something new. My advice is, "LET IT GO!" Stick it in a drawer, move on. Trust me, you will get better just by virtue of experience, and if you turn out to be Ernest Hemingway twenty years down the line, they'll ask you what you have stored away in that drawer of yours.