Surface interaction at the biomaterial–cell interface is essential for a variety of cellular functions, such as adhesion, proliferation, and differentiation. Nevertheless, changes in the biointerface enable to trigger specific cell signaling and result in different cellular responses. In order to manufacture biomaterials with higher functionality, biomaterials containing immobilized bioactive ligands have been widely introduced and employed for tissue engineering and regenerative medicine applications. Moreover, a number of physical and chemical strategies have been used to improve the functionality of biomaterials and specifically at the material interface. Here, the interactions between materials and cells at the interface levels are described. Then, the importance of surface properties in cell function is discussed and recent methods for surface modifications are systematically highlighted. Additionally, the impact of bulk material properties on the cellular responses is briefly reviewed.