Several different lists of best 50 or best 100 SF novels can be found at the interesting site Sci-Fi Lists. Of course, most of these are well known to SF enthusiasts. Here are some extra novels you've probably never heard of but which I enjoy re-reading every 10 years. Listed in chronological order.
Only a brave fool would declare one book to be the best of classic hard SF, but I nominate this as the most representative. No sex, gratuitous violence or mysticism. In the "Engineering confronts Mystery" style of 2001: A Space Odyssey, but without the latter's pretension: a well-written and engaging story line.
I have a fondness for "Pacts with the Devil" stories, but most turn out too corny or too like B horror movies. Blish develops a stunningly original idea: what would sorcery be like if it really worked as described in medieval grimoires? Recall Shakespeare's I can call spirits from the vasty deep; a modern-day Faust finds out what happens if they do come. Imagine C.S. Lewis without preachiness.
A city winched along tracks perpetually relaid across an earthlike planet with a hyperbolic-shaped sun. Call me crazy, but I love this premise.
The most underrated SF novel of the century. On a reservation within a stagnant overcrowded industrial human society live the Ler, an offshoot species who are physically only slightly different from humans, but psychologically more different and with a substantially distinct culture. The novel paints an amazingly well-developed picture of their society and culture, making other such attempts (e.g. Sawyer's Neanderthals) seem sophomoric. Decentralized Ler society contrasts with the machinations of the authoritarian-rationalist human government bureaucracy. And the underlying plot, which I won't spill, recalls the Glass Bead Game. The book is part of a series reissued in 2006 as Book of the Ler. Ironically most readers assume the author was female but it turns out (cf. machinations above) he was in U.S military intelligence.
I'm not a big fan of fantasy, but this is an engaging "rationalized fantasy" tale of diverse creatures on a Quest. Charming without being stupid, sentimental or portentous.
Carver's other books seem rather hackneyed but this one hits the spot. Scientist discovers he has ordered spaceship to be built but can't remember why .... Well-paced plot twists that you can't predict.
The most satisfying of the numerous daring SF ventures into the artificial intelligence/artificial life topic. Virtual reality, popularized by The Matrix, is just artificial sensory inputs into your real brain. Egan is concerned with two different ideas. One is software copies, the idea that a mind can be uploaded into a software environment that the mind perceives as realistic (and that survives after the real person's death), and that real people can communicate with copies via an interface. The second is the cellular automaton; if one accepts the implausible idea (Wolfram et al.) that the real universe is a cellular automaton, then maybe you can simulate your own simpler-rules automaton in software to create an artificial universe in which native creatures evolve and human minds can be embedded. Neither idea is completely new but Egan has thought harder than most about the implications and written it as a novel. Like Asimov, not much character development.
A different take on the well-worn feudalist theme: treachery and chivalry with airplanes in a low-tech future Balkanized by whales (sic). Complex plot, large cast of characters; part of the Greatwinter Trilogy. Comparable to Martin's Ice and Fire series but more creative in concept and less formulaic in execution.
A near-future hard SF story that paints an unforgettable image of the subjective experience of being a high-functioning autistic adult.