Exploring the cell-material interface is an emerging area of great interest in biomaterial science. Specifically, creating nanostructured surface interfaces to improve biomaterial efficacy is one of these key focus topics. As an example, an increasing number of studies have demonstrated the positive role nanostructured surfaces can have towards promoting various cell functions. However, the relevant mechanism behind this improvement in biological interactions at the cell-implant interface is not well understood. For this reason, here, osteoblast (bone forming cells) and fibroblast (fibrous, soft tissue forming cells) functions (including adhesion and proliferation) on two carefully fabricated diamond films with dramatically different topographies were tested. The results revealed greater cell responses on nanocrystalline diamond (grain sizes <100nm) compared to submicron crystalline diamond (grain sizes 200-1000nm). In order to understand this positive impact of diamond nanotopography on cell responses, fibronectin absorption and subsequent cell spreading were studied. More importantly, cell filopodia extensions were also studied through computational mechanical modeling. A deflection-diffusion model of cell filopodia extension was established and clearly suggested that increasing the lateral dimension or height of nanometer surface features could inhibit cell filopodia extension and decrease cell spreading. Both the experiments and modeling from this study indicated that a nanometer surface topography can enhance cell responses to promote implant efficacy. © 2010 Materials Research Society.