This actually came up as a comment on a blog post I wrote about Cutting the Apron Strings.
I think the logical answer to this question is yes, but then I think back to the story I shared about client Shelley Coriell and some of our own submission stories about books we wouldn't give up on. Do you know that I once had a proposal sit on an editor's desk for two years before I got an offer?
There are two answers to this question for me. The first is that you stop querying when you know it's time. People often say, "you'll know" about a lot of different things in life. Usually unpleasant things. Although it's cliche, I do think it's true. We usually know when enough is enough with something. The real struggle is admitting it.
The second answer is when you start querying your next book. The minute you start querying you've put that book away and have started work on the next book. If you haven't, you better. This means you're busy doing two things at once. Sending out queries, and maybe reworking that query letter a few times, and writing the next book. You are NOT rewriting the book you are querying. Once you start querying it's too late for that. If you haven't received an offer by the time the second book is ready to go out it's time to put the first book to rest.
Presumably you've learned a lot from the query process and your own writing so it would be a shame to continue to query the weaker of what are now your two books.
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