That's not a particularly easy question to find an answer for.
In SOME respects, it's easy.
For example, you MUST KNOW that any hugely popular book is going to be followed by a plethora of similar stories sent in to short story markets. Every release of a new Twilight book is followed by an avalanche of vampire stories.
You must also know that some story frameworks are so old and oft-done that finding a unique angle to them is a challenge for even the best writers. The standard romance motifs, for example. You know them. Jane Austen did them all. 1) Boy meets girl; boy hates girl; girl hates boy; they find they've misunderstood each other and reconcile in the end. 2) Boy loves girl; girl loves boy; boy and girl torn apart by circumstances beyond their control; boy finds girl in the end. 3) Boy meets girl; boy and girl love each other but bumble around with telling each other so; finally in a moment of tension boy confesses to girl. 4) Any combination of the above. Also, the speculative fiction standards--werewolves, vampires, dragons, evil aliens, fairy tales. That last one's my nemesis. I love writing 'fairy tale riffs,' as one editor described them. But they're hard to sell.
It is a truth that no story is wholly unique. Every story has been told, every angle explored. But your story still has to be unique in some way.
Maybe it's uniquely well-written.
Or uniquely deep in characterization.
Or unique in it's setting. Sometimes the most mundane settings can be the most unique, which further complicates things, doesn't it? But really, how many stories are set in New York City? A lot. Loads of interesting things happen in New York, but that's to be expected, isn't it. How many stories are set in a housewife's kitchen? Could you create an interesting story set in a housewife's kitchen? Something like Irma Splinkbottom's Recipe for Cold Fusion? (by Janene Murphy, Flash Fiction Online, November 2009)
Maybe your story has a unique twist to an old theme, like a vampire whose mortal buddies let him suck a little blood once in awhile because the poor kid gets so darned pale and listless (Ray the Vampire by Mercedes M. Yardley, Flash Fiction Online October 2008).
Maybe your story uniquely emphasizes a culturally or societally relevant theme in an oft-repeated story framework, such as prejudice and genocide in The Three Billy Goats Gruff (Trip Trap by ME, Anotherealm May 2005).
Understand that some story ideas that don't sell are hard to pin down because you don't see any of them in the fiction markets. So, naturally, you think, 'My story is different from all those published stories, so it's SURE to sell.' Think twice about that one. Many publishers include in their guidelines lists of story ideas they see too often or don't want to see. Read those lists. Keep them on file. If THOSE publishers are seeing those story ideas too often, so are ALL publishers.
Here are two from Strange Horizons:
Stories We've Seen Too Often
Horror Stories We've Seen Too Often
Here's one from Thrilling New Detective Fiction:
In addition to these, I'll add my own observations of what we're unlikely to publish.
*Suicide. I'd rather see characters acting to save themselves, even if they fail miserably.
*Abuse of children, especially sexual abuse, ESPECIALLY incest. Yes, it's an important issue, but it needs to be dealt with in a very serious way, not in some fiction magazine on the internet.
*Granny (or Pappy) is dying. I love grandparents as much as the next guy, but it's hard to make it anything but depressing, and it's hard to do it in a way that hasn't already been done a million times before.
*An all-encompassing Depressing S**t (to quote an editor friend) category.
*Stories told from the POV of a cat (or dog, but especially a cat--personal bias), especially if the fact that the POV character is a cat (or dog) is withheld from the reader until the end.
*Bad relationship stories. Too often such stories are about dumb people who suffer abuse or unhappiness because of their own stupid choices. Why would I want to read about that?
*Erotica and excessive pointless violence. There are markets for those. Markets that are NOT for those kinds of stories don't want to read them.
Another way to figure out what might sell is to read--and read a lot.
You'll find dozens of free online fiction magazines in all genres. Some of them, like Every Day Fiction, will send the stories right to your email inbox.
But don't make the mistake of reading a story about a little boy on a trampoline and think your own story about a little boy on a trampoline will sell to the same magazine. We not only want something unique, we want something that hasn't been done before. We don't want to bore our readers with too many similar stories. We want every story to be a new and exciting literary feast.