An ideal surface for many biomaterials applications would resist nonspecific protein adsorption while at the same time providing a means for specifically signaling cells to guide survival, growth, migration, and differentiation. This work was directed towards the investigation of model systems and clinically-applicable materials which provide both of these surface requirements. Model systems were prepared by chemically grafting end-functionalized star poly(ethylene oxide) (PEO) to surfaces. The end-grafted polymers provide a means for cell-signaling through coupling of peptides to the free chain ends. Protein adsorption on star vs. linear grafted layers was compared. To further understand these results, neutron reflectivity studies were carried out in situ for solvated PEO surfaces to determine the concentration profiles of the swollen grafted layers. Surprisingly, grafted PEO layers which resist protein adsorption have low concentrations of polymer segments throughout the swollen layer. We find that dense star architectures which might be expected to impart improved protein resistance in fact allow small proteins to adsorb. For clinical materials, a novel approach to the surface modification of poly(lactide) (PLA) has been taken by surface segregating a comb copolymer containing a PLA backbone and poly(ethylene glycol) teeth. The ends of the teeth provide sites for surface tethering of peptide ligands. Comb surfaces without tethered ligands are cell adhesion resistant, indicating strong protein adsorption resistance. By then incorporating an adhesion ligand, modulation of cell morphology on comb surfaces has been demonstrated. Finally, the surface segregation of the comb to the surface of PLA was shown via cell attachment assays and XPS measurements.