An increasing number of studies have demonstrated the positive role nanotopographies can have toward promoting various cell functions. However, the relevant mechanism(s) behind this improvement in biological interactions at the cell-material interface is not well understood. For this reason, here, osteoblast (bone forming cell) functions (including adhesion, proliferation, and differentiation) on two carefully-fabricated diamond films with dramatically-different topographies were tested and modeled. The results over all the time periods tested revealed greater cell responses on nanocrystalline diamond (NCD, grain sizes <100 nm) compared to submicron crystalline diamond (SMCD, grain sizes 200-1000 nm). To understand this positive impact of cell responses per stiff nanotopographies, cell filopodia extension and cell spreading were studied through computational simulations and the results suggested that increasing the lateral dimensions or height of nanometer surface features could inhibit cell filopodia extension and, ultimately, decrease cell spreading. The computational simulation results were further verified by live cell imaging (LCI) experiments. This study, thus, describes a possible new approach to investigate (through experiments and computational simulation) the mechanisms behind nanotopography-enhanced cell functions. © 2011 Wiley Periodicals, Inc.