Biocompatibility is key to the performance of any material in a biological environment. This review outlines current opinion on the factors that lead to biocompatibility and focuses on the interactions that occur at the interface between material and environment. The sequence of events, from protein adsorption, cell attachment and behavior, to biocompatibility, is traced. Although these processes are studied and reported widely, there is, as yet, little published evidence that implant biocompatibility can be enhanced in the long term by surface engineering. This lack of evidence does not necessarily imply a lack of effect, but may be ascribed to a lack of robust characterization and poor modeling of the implant environment.