Nanostructures have a profound effect on cellular behavior. Nanostructures have been shown to effect cellular adhesion, proliferation and differentiation in a myriad of cell types in various ways. Cells interact with nanostructures as small as 10 nm; however there is not a clear understanding of whether cells interact with anything smaller. In this study we investigate the role that sub-10nm sized features play oncellulargrowth and morphology by comparing the growth and morphological responses of MDCK epithelial cells and NIH3T3 fibroblasts cultured on an ultra-flat/atomically flat, “nanosmooth”Silicon (Si) Wafer and a “nanorough”Glass coverslip substrate. We have found that loss of sub 10 nm features results in profound alteration to the growth of MDCK epithelial cells and alters cell morphology and actin cytoskeletal organization. Theseresults demonstrate the importance of considering nanoscale structure, even irregular structure, during device design.