In terms of biomaterial development and implant technology, the cellular response can be affected by topographical circumstances. In the field of in vitro cell biology, there is a growing body of data that shows how cells respond positively to substrate topography, particularly in the nanoscale regime. The role of a substrate is more than merely providing mechanical support; it acts as an intelligent surface providing physical, chemical and topographical signals, which guide and control cellular behavior. Fabricating nanostructures on surfaces provides features that are on the same scale as cellular features and biological entities. Influencing cell behavior using substrate nanotopography is an attractive strategy for regenerative medicine applications and advanced tissue engineering. New fabrication technologies and new nanotechnologies have provided biomaterial scientists with enormous possibilities when designing customized tissue culture supports and scaffolds with controlled nanoscale topography. The goal is to effectively design scaffolds by choosing the appropriate combination of biomaterials, surface chemistry, geometric design, and physical properties to be able to (a.) tailor towards applications as challenging and complex as stem cell differentiation and to be able to (b.) release incorporated biomolecules for therapeutically enhancing cellular environments. This work has emphasis on the observed effects of nanostructured surfaces on various cell behaviors, specifically morphological modulation, enhanced functionality, and guided stem cell differentiation into lineage specific cell types using nanotubes and nanopillars. Additional discussion will focus on sustained, improved bioavailability of drugs incorporated in surface nanostructured “motherships” for long term drug release. Lastly, new scaffold topographic designs and surface structure variations are considered with unique approaches to further i) control cell behavior for tissue engineering therapies and implant designs and ii) tailor release of biomolecules for therapeutic applications.