It's rarely about whether or not the story will hold up, although I do spend time beating my head against the first line/first paragraph/first page wall. It's all about that darned cover letter. When I get my first pro sale, though, I'll finally have something to say other than here's my story, thanks for your time.
At the INK meeting we listened to some great podcasts about writing. One thing new I picked up that I hadn't thought about much before is the sorting process that incoming manuscripts go through. The podcast speaker (the wonderful Gardner Dozois) said that many (not all) editors sort the incoming manuscripts into piles which then get the following treatment. The slush pile, being the largest, gets the most cursory look. Sometimes all you get is two lines. It's a slush pile reader survival thing. Yes, perfectly good stories get passed up but that's the nature of the beast. If the reader gets to the end of the story it goes on the okay or maybe pile. The semi-pro and pro (sometimes they're on two separate piles) get a much more 'fair' shake. Still no guarantee of publication, of course, but the reader will probably give them a whole page to distinguish themselves.
One way to get out of the slush pile and into the semi-pro pile is to have something interesting in the cover letter. A sense of personality in the cover letter is a bonus too, as long as you don't make yourself sound like a crazy person or come off as obnoxious. A professional credential, no matter how tenuous, like if you studied sea stars in college and the story is about intelligent sea stars taking over the ocean, sometimes helps too. The fact that you met the editor at a small press party and you had fun discussing fine wine and cheese pairings can help, but you'd better be sure that the editor had fun and bear in mind that some editors don't like things like that mentioned in cover letters unless the editor invited you to send in a manuscript. Now why would this last item help? If the editor had fun talking with you then that editor knows that you're not crazy, that you're polite, and you might be easy to work with. Given a choice between two stories when one is written by a known pain in the you-know-what and the other enjoys the same single malt scotches as you and is respectful without being cultishly in awe, the scotch drinker will get the sale, right? Right.
Another podcast (this one by Shawna McCarthy) discussed the odds of getting published. I've heard the numbers spelled out before but this time I was heartened. 90% of the stuff in the slush pile is unpublishable. That's great news! I don't believe I'm unpublishable, though of course I could easily be deluded. The point is that if I'm right about where I'm at on the scale of all things slush, I'm really only competing with 10% of what's in the slush pile. That's much, much better odds. Out of 300 manuscripts a month, for example, I'm only vying to get into the okay pile with 30 of those. I can live with that, and I don't feel badly about not out-competing those so far. Actually, I can't say that. I've been blessed with the knowledge that I've made it into the pile for the final cut before. That's even more heartening.
So I'm feeling better about cover letters, I'm happier with my odds, and I'm looking forward to submitting on a regular basis. It's a different kind of persistence than I've felt before. It isn't something I force myself to do. In fact, it's kind of fun!