Among science-fiction authors, Orson Scott Card is one of the most accessible to readers who are not science-fiction fans, and he has frequently jumped genre boundaries to write horror, religious fiction, and fantasy.

Some good places to start are: Ender's Game and Speaker for the Dead, Lost Boys (horror), Stone Tables (religious fiction), Treason, and Wyrms.

I recommend avoiding: the entire "Ender" series except Ender's Game and Speaker for the Dead, The Worthing Saga, and the "Homecoming" series.

Orson Scott Card is a historian as well as a Scifi author, and if you are interested in history, I strongly suggest his very excellent and unique view of Christopher Columbus in Pastwatch, as well as Shadow of the Hegemon for its interesting glimpses into the past in addition to the future.

I would strongly, strongly recommend for readers new to OSC to AVOID Wyrms, Hart's Blood, or his collection of short stories, unless you wish to read them for their horror value. I also suggest avoiding all of the Ender's Game series except for the truely excellent Ender's Game until you are more familiar with his work. Do not read Children of the Mind unless you have read the other Ender's books.

Ender's Shadow is one of his best books, as is Enchantment for a more romantic look at things. Songmaster is very good for those looking for truly interesting and unique worlds (as is Treason, but this again is somewhat more horrific than the usual fantasy fare).

Magic Street is a great black Shakespearean-punk sort of novel, and I recommend that for fans of Neil Gaiman, as it is written very much in his style.

Card is among the most consistent and excellent writers of sci-fi/fantasy currently writing. I love the Ender Wiggin series, but heartily recommend reading it in the order published. You'll be totally out of your depth otherwise.
I also enjoyed the Seventh Son series, although it faltered in the last book or two.
Some of his off-genre books are a little odd, but the only thing of his I've read that I didn't enjoy was "Homebody." Well, "Folk of the Fringe" is a bit odd too. :}
His short fiction is good, and I disagree that it wouldn't be an appropriate place to start. If you're the sort who is put off by a big long series like Ender, then by all means start with the short stories to see if you like his style.

I also enjoy his Biblically-based fiction, even if I don't agree with every liberty he took in the stories.

All in all, you're unlikely to go wrong with Card.