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The interaction of mammalian cells with nanoscale topography has proven to be an important signaling modality in controlling cell function. Naturally occurring nanotopographic structures within the extracellular matrix present surrounding cells with mechanotransductive cues that influence local migration, cell polarization, and other functions. Synthetically nanofabricated topography can also influence cell morphology, alignment, adhesion, migration, proliferation, and cytoskeleton organization. We review the use of in vitro synthetic cell–nanotopography interactions to control cell behavior and influence complex cellular processes, including stem‐cell differentiation and tissue organization. Future challenges and opportunities in cell–nanotopography engineering are also discussed, including the elucidation of mechanisms and applications in tissue engineering.