The biocompatibility of medical implants dictates the fate of almost all medical devices. It is well established that medical devices trigger a variety of adverse tissue responses, such as inflammation, fibrosis, infection and thrombosis. However, the mechanisms involved in biomaterial-mediated tissue responses remain largely unknown. The lack of such knowledge hinders the development of biomaterials with better biocompatibility and safety. The aim of this review is to summarize our current understanding of the processes governing foreign body reactions to tissue-contact devices. Obviously, this information is urgently needed for assisting the rational design of materials or medical devices to minimize undesirable tissue reactions upon implantation and, in addition, to promote the wound healing process.