William Gibson. SF was all abuzz from the the late 60s through the 70s about the 'New Wave' SF writers. Some were very good, like Thomas Disch, and Harlan Ellison. There was endless chatter and argument over whether the New Wave or more traditional SF storytelling would rule the future of SF. But SF writer who has had the most impact on the consciousness of the book-buying public over the past thirty years is neither a traditionalist nor a New Wave writer. Thirty years after Neuromancer, Gibson's novels still make the general interest best seller lists. Gibson did it by merging the existing, well-worn thriller/detective/spy genre, with science fictional concepts and a contemporary, cosmopolitan flavor.
J.K. Rowling. The Harry Potter books are a melding of the English public school novel with common fantasy tropes.
Jos Whedon. Buffy is a melding of the teen drama, like Beverly Hills 90210, or The OC, with vampires, and other fantasy material. Firefly, of course, was an attempt to meld the western with SF. (Which shows that the melding of spec fic with another genre does not guarantee success. Of course, Whedon was not the first to think of this particular mix, either.)
George Lucas. Star Wars, as you know, Bob, is a loose re-telling of Kurosawa's The Hidden Fortress. In other words, it retold an action-adventure story of derring-do with SF furniture. Lucas was not the first to do this: what else was the original Flash Gordon series? But Lucas was the first one to do it well, with a big budget and revolutionary special effects.
China Miéville. The City and the City is a melding of the police procedural detective novel with alternative history fiction, which is usually classified as a subset of spec fic. (It's also what the Turkey City Lexicon calls a 'Second Order Idiot Plot', which stands as evidence for what many have suspected, that anything that the TCL denounces as bad writing can, in skilled hands, be good writing.) I give Mieville as an example because his novel was published very recently. I doubt that The City and the City will be as wildly popular or considered as groundbreaking as Neuromancer, but at the very least it has been well received, and is currently on the Nebula ballot.
Finally, paranormal romance. I don't know who invented it, but it is very successful, and it hardly existed a decade ago.
Thus: if you want to write spec fic, and you want to leave your mark not just on our little ghetto, but on the history of Western fiction, I suggest that you try to merge an existing successful genre with spec fic ideas and setting.
That naturally leads to the question: what genres are left to work this trick on?
I'm still thinking about that. And BTW, if I had it figured out, I certainly wouldn't tell you, I'd write it myself, and be off to fame and fortune. (Or I'd write it cheezily, like Flash Gordon, and my work would be remembered as a joke for decades, until a George Lucas came along, did it right, and changed the world. Merely knowing what to do is not enough. Execution is equally important.)
However, I can throw out a few of suggestions that I can't or won't use.
1) Chick lit. Chick lit is wildly popular and successful. For one thing, it sometimes feels that 'chicks' are the only ones who read any more. Consider Bridget Jones's Diary, Sex and the City, or Confessions of a Shopaholic. How could these be reimagined as fantasy, or SF?
2) Tom Clancy techno-military thrillers. There have been attempts at this before -- Heinlein's Starship Troopers comes to mind as does lots of modern military SF. But my impression is that most military SF is more SF than it is military. Starship Troopers, whatever its virtues, isn't much like Tom Clancy. I predict that the person to do this melding right will reap fame and fortune. But it ain't me.
3) Christian literature. The field of Christian literature is huge, and unsuspected by most of the educated elite. Yes, that includes me. I know little of this literature, but it's there, in thousands of Christian bookstores around the nation which aren't even included in the NYT bestseller numbers. Christian SF has been attempted many times: C.S. Lewis's 'Space Trilogy', A Canticle for Leibowitz, and most recently the Left Behind novels are examples. Lewis's novels are still read, although 'Liebowitz' never made much an impact outside SF. The Left Behind novels were fabulously successful, even if (they have been reported to be) not well written. 'Christian literature' is arguably a theme not a genre, but I think it's wide open for the spec fic writer.