Many people would probably throw their lot in with Card's Ender's Game or maybe something less spacy like Children of Men. Some will probably go old-school with Stranger in a Strange Land or A Childhood's End. A Brave New World? However, what many of those novels lack is a modern, topical tale written on the grandest scale imaginable. My choice, of course, is Dune, by Frank Herbert.
Set in a galaxy unrecognizable yet strangely familiar (planets seem to be conveniently divided by earth-like biomes), this novel is an epic on par with any historical war novel or sci-fi space opera out there. It covers the Machiavellian posturing of several Great Houses within a Galactic Empire that depends on a rare and precious fuel: the spice, melange. The spice allows the space travel that covers the known galaxy, and literally provides the groundwork for every economical, social, and political system within the empire. However, this spice is only found on one planet, a desert planet known as Arrakis, and there is going to be a change in control from the militaristic and violent House Harkonnen to the more politically stable House Atreides.
Arrakis is a dangerous planet, with violent storms and leviathan sand-worms that can destroy entire cities. The House that controls Arrakis controls the spice, however, and becomes an instantly powerful entity in the galaxy. Other than being the source of all galactic space travel, the spice imbues those that ingest it with special powers. However, only women have been able to accomplish this without dying form its poisonous properties. There is a legend (as there always is) that there will come a time when a man will survive this process and he will rise up to destroy the empire and become a God. Enter Paul Atreides, the protagonist of the story and a young man favored and feared to become that legendary one.
This book is both didactic and incredibly entertaining. I swear for Herbert to have written this when he did, he would have to have been clairvoyant. The themes, the plot elements, even the language and names are all analagous of modern global issues. A precious fuel, found under the sand of desert, the control of which is hotly contested by many nations? Sound familiar? Even the wording and the stoic, native peoples of the desert are largely from middle-eastern cultures. The religious framework of the book is definitely an allegory to the monotheistic religions of today.
Even the young protagonist is a blatant Christ-figure, though without the crucifiction. And therein lies the brilliance of Frank Herbert. Without giving too much away of the first book, Herbert went on to write at least four more novels that follow the thread of this first one. In those novels Herbert takes an already broadly sweeping epic and stretches it along an incredible timeline that is an allegorical illustration of how mankind build nations, founds religions, preverts their institutions, and eventually crumbles to be reborn by something else not altogether different than what was overthrown in the first place. Call it the cycle of civilization, but you have the very balance of it in Frank Herbert's Dune.
Incidentally, the novel is now free online. There has been two efforts to make a film about the book. David Lynch (of the Blue Velvet and Mullholland Drive weirdness) directed a brilliant film adaptation of the novel the perfectly captured, I feel the book. The Sci-Fi Channel attempted a miniseries that, as many Sci-Fi original movies tend to do, missed the mark by a mile (The first twenty minutes or so is manageable thanks to William Hurt.) However, even as bad as that mini-series was, I still bought the dvd set! The Dune story is so incredibly engrossing, so fantastical yet applicable to our modern circumstances, that I bought the Sci-Fi original miniseries. Further proof? George Lucas stated that Dune was his inspiration for the Star Wars universe, and we know how well that went over.
For these reasons, and many others that have yet to be understood by those of you that haven't read it yet, Dune is the "Best Sci-Fi Novel Of All Time".