Implantable medical devices are increasingly important in the practice of modern medicine. Unfortunately, almost all medical devices suffer to a different extent from adverse reactions, including inflammation, fibrosis, thrombosis and infection. To improve the safety and function of many types of medical implants, a major need exists for development of materials that evoked desired tissue responses. Because implant-associated protein adsorption and conformational changes thereafter have been shown to promote immune reactions, rigorous research efforts have been emphasized on the engineering of surface property (physical and chemical characteristics) to reduce protein adsorption and cell interactions and subsequently improve implant biocompatibility. This brief review is aimed to summarize the past efforts and our recent knowledge about the influence of surface functionality on protein:cell:biomaterial interactions. It is our belief that detailed understandings of bioactivity of surface functionality provide an easy, economic, and specific approach for the future rational design of implantable medical devices with desired tissue reactivity and, hopefully, wound healing capability.