The need to control the adhesion of cells to material surfaces plays an important role in determining the design of biomaterial substrates for biotechnology and tissue-engineering applications. As a the first step in a cascade of cellular events, adhesion affects many aspects of cell function, including spreading, migration, proliferation and differentiation. After a short description of cell adhesion and essential molecules involved in, the present knowledge on the influence of surface topography on cell behavior will be described by considering not only the amplitude of the surface topography but also its organization at all scales (micro- and nano-scale). The biological mechanisms underlying the cell response to topography will be evoked. Secondly, the influence of surface chemistry as well as surface energy on cell adhesion will be described. Thirdly, as the cells never interact with a bare material but with materials on which the proteins from biological fluids have adsorbed, some studies on the role of proteins in cell adhesion will be used to illustrate this point. Finally, the influence of substrate mechanics on cell differentiation will be described. (C) Koninklijke Brill NV, Leiden, 2010