The integration of biomaterials with skin is necessary to enable infection-free access to vasculature and body cavities. Also, integrating plastics and metals with skin increases options for the reconstruction of surgical and traumatic defects and enables the permanent implantation of robotic and electronic devices. Until now, attempts to integrate biomaterials with skin permanently have failed because of epidermal marsupialization and infection. This article reviews the general properties required of biomaterials to optimize integration with body tissues, the modifications that increase biocompatibility, focusing particularly on surface functionalization and the specific requirements for biomaterial integration into skin. Critical pathophysiological processes relating to biocompatibility are discussed with particular emphasis on the skin-biomaterial interface. Future directions are speculated on, in particular, the specific utility of subatmospheric pressure dressings in facilitating tissue integration into biomaterials.