Did some thinking about this. It seems to me that setting can be dictated by the story that you tell. I mean there is a completely different feel from NYC to San Franciso, Seattle to New Orleans, Chicago to Miami. If you have a midwest mindset to your story, I do think you have to be true to the story.
Brings to mind the old song, "New York State Of Mind". I've always had trouble really figuring the idea out in detail (probably because I've never been closer to the Big Apple than somewhere in eastern Pennsylvania), but I have acquired an appreciation for the difference between, say, San Francisco and Los Angeles. The real trick is, as Meg points out, establishing the 'feel' for a given locale.
I guess the next question would be to try and imagine the story playing out somewhere else. Does that affect the flow? For example, the Dresden stories mostly take place either in real-world Chicago or the Nevernever. If Jim downed an injudicious quantity of, say, mojito, and set a story in Miami, it might allow Thomas a chance to hog the spotlight a bit more than he already does, but Harry would be absolutely miserable in his spellworked coat. (And Mouse would be equally miserable in his perfectly natural coat, but I digress.) The most important point, though, is that Harry simply
fits better in Chicago, with its layers of physical constructions mirroring the social and magical landscape, which in turn mirrors Harry's own complexities.
Wandering back to the topic, see if you can get a grip on the 'look and feel' of your chosen setting. See if you can determine what about your vision of the setting sets it apart from anyone else's, especially the intangible elements. Is there a particular neighborhood or building that consistently gives you a particular emotional reaction? Are there any urban legends that really capture your attention? Even if you can't use them in your stories without jumping through copyright laws, are there particular songs you associate with the setting or components thereof? (You can play them in the background while you write; can do amazing things with the 'themes and moods' of your drafts.)
Good luck!