Biomaterials play a central role in modern strategies in regenerative medicine and tissue engineering to restore the structure and function of damaged or dysfunctional tissue and to direct cellular behavior. Both biologically derived and synthetic materials have been extensively explored in this context. However, most materials when implanted into living tissue initiate a host response. Modern implant design therefore aims to improve implant integration while avoiding chronic inflammation and foreign body reactions, and thus loss of the intended implant function. Directing these processes requires an in-depth understanding of the immunological processes that take place at the interface between biomaterials and the host tissue. The physicochemical properties of biomaterial surfaces (charge, charge density, hydrophilicity, functional molecular domains, etc.) are decisive, as are their stiffness, roughness and topography. This review outlines specific strategies, using polyelectrolyte multilayers to modulate the interactions between biomaterial surfaces and biological systems. The described coatings have the potential to control the adhesion of proteins, bacteria and mammalian cells. They can be used to decrease the risk of bacterial infections occurring after implantation and to achieve better contact between biological tissue and implants. In summary, these results are important for further development and modification of surfaces from different medical implants.