How many rejections are enough?

Last week on Twitter, an aspiring author friend threw out this question:

How many rejections is enough? When is it time to hang the manuscript up?

She got quite a few answers, and they ran the gamut from now to never.

But the one the answer that stopped me was:

when you've queried the pubs/agents you're interested in working with/respect & the answer is always no, it's time

Yeah . . . no. Here's why that doesn't work for me.

1) Think of the stories told over the years by authors who suffered...