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The physical characteristics (i.e., nanostructure and stiffness) of the extracellular matrix where cells reside have been shown to profoundly affect numerous cellular events in vivo and also been employed to modulate cell behavior in vitro, yet how these physical cues regulate cell behavior is still elusive. Therefore, we engineered a variety of nanotopographies with different shapes and dimensions, and investigated how the nanotopographical cue, through focal adhesions-cytoskeleton-nucleus pathway, affected cell phenotype and function. We further designed and fabricated well-defined substrates which had either identical biochemical cue (adhesive ligand presentation) but different nanotopographical cues or identical nanotopography but different biochemical cues, and dissected the roles of these cues in cell modulation. In addition, we revealed that the human mesenchymal stem cells (hMSCs) could obtain nanotopographical memory from the past culture environment, and the nanotopographical memory influenced the future fate decision of the hMSCs. Moreover, we evaluated the effects of substrate nanotopographical and stiffness cues on the fibrogenesis of human lung fibroblasts in response to carbon nanotubes and highlighted the significance of these physical cues in the development of physiologically relevant in vitro models for nanotoxicological study. The mechanistic understanding of the physical regulation of cell behaviors will provide important insight into the advancement of cell culture technologies and the recreation of biomimetic in vitro tissue/organ models.