Tetris for its great simplicity in the 2D-era, Portal for its great simplicity in the 3D-era, and Braid for the most exploration of how much further video games can go than we often do today.
All three are puzzle-games I love (Portal/Braid) or enjoy (Tetris), but I don't really consider myself a big fan of the genre...odd.
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Nominate E P O N A.