This chapter gives an introduction to the tools and the background knowledge for further studies of cell-substrate interactions. A cell adhesion test is presented by which it is possible to study the functional behavior of specific proteins after adsorption. The test used model surfaces, cycloheximide treatment, fluorescence microscopy and divalent cations (Mg2+/Ca2+) for cell quantification, cell morphological studies and monitoring of specific/non-specific cell-substrate interactions.Four plasma proteins, ceruloplasmin, prothrombin, 2-HS-glycoprotein and 1-antichymotrypsin, have been investigated. The goal was to monitor their orientation and (if possible) conformational changes after adsorption and to study their influence on bone cell adhesion as a result of the adsorption process.The study was performed on ultraflat model surfaces (silicon wafers with a natural layer of silicon oxide/silica) to be able to characterize the adsorbed proteins with atomic force microscopy (AFM) and ellipsometry, and to single out the protein-induced effect on the cell activity by reducing interfering surface properties (e.g., topography, variations in surface chemistry). The dimensions of the adsorbed proteins on silicon wafers were measured with the AFM and the values were compared with available X-ray data. The molecules appeared to be oriented with their long axis parallel to the surface or, as in the case of ceruloplasmin, with one of its larger sides towards the surface.