Anchorage-dependent cells in t he body require ad hesion to t he solid extracellular matrix (ECM) for normal function (Benzeev et al., 1980; Girard et al., 2007; Ingber, 2006; Re et al., 1994). e ECM consists of brous networks composed of proteins such as bronectin, laminin, vitronectin, collagen, and elastin (Vakonakis et al., 2007). ese structures provide physical and chemical signals at the nanometer length scale t hat control cell f unctions such as migration, proliferation, a nd apoptosis (Ingber, 1990; Girard et al., 2007; Stevens et al., 2005). e ECM in the body can be mimicked in vitro by fabricating materials that present de ned chemical and physical signals to t he cell (Chen et al., 1997; Clark et al., 1990; Flemming et al., 1999; Lo et al., 2000; Schnell et al., 2007). In particular, manipulating cell adhesion by fabricating material surfaces with nanoscale structures has emerged as a promising approach to control cell function both in vivo (Webster et a l., 2000; Zhang et a l., 2008) and in vitro (Dalby et al., 2008; Liliensiek et a l., 2006; Sniadecki et a l., 2006; Teixeira et a l., 2006; Yim et a l., 2005). Fabricating biomedical implants w ith na nostructured surfaces can a llow t he selective control of cellular interactions with the implant which is desirable for optimal implant performance. While it is clear that cells are exquisitely sensitive to nanostructured surfaces, the molecular mechanisms that determine this sensitivity are less clear. is chapter focuses on the current understanding of the mechanisms by which cells sense the nanoscale structure at the molecular level and how this understanding can be useful in developing novel antifouling materials.