Influencing cell behavior from proliferation to differentiation using substrate or implant topography is an attractive strategy for regenerative medicine applications. Substrate topography at the submicron range is of particular interest because the size range is comparable to extracellular matrix structures. Emerging literature presents many interesting findings on how nanotopography enhances cell adhesion, alters cell morphology, affects proliferation, initiates intracellular signaling, provides contact guidance and mediates stem cell differentiation. Incorporating topographical consideration into the design of a biomimetic microenvironment for cell culture will become increasingly important in light of these studies and practical with advances in nanofabrication technologies. This Highlight underscores the promise of and the unknown information about topographical effects in manipulating cell-substrate interaction and advancing tissue engineering.