This paper addresses a significant paradox in biomaterials science; biocompatibility phenomena have been experienced and described for over 50 years but without an agreed understanding of the framework of mechanisms that control the events that occur when a biomaterial is exposed to the tissues of the human body. The need for such an understanding has become more urgent as biomaterials are now used in wide-ranging applications such as tissue engineering, drug and gene delivery, and imaging contrast agents. A detailed analysis of these phenomena, especially in terms of clinical outcomes rather than in vitro experiments, determines that two overarching mechanisms, mechanotransduction and sterile inflammation associated with damage associated molecular patterns, are responsible for the vast majority of phenomena. In contrast, interfacial interactions, for so long being assumed to play pivotal roles in biocompatibility, especially relating to protein adsorption, are actually relatively unimportant unless, through conformational changes, they are able to participate in 3D ECM development. Critical to this new view of biocompatibility is the fact that the combination of mechanotransduction and sterile inflammation, especially focusing on inflammasome activation and the immunology of the balance between inflammation and fibrosis, allows biomaterials science to encompass mechanisms of innate and adaptive immunity without recourse to the traditional implications of pathogen induced responses of the immune system. In this way, a system of biocompatibility pathways can be generated; these are able to explain a wide range of clinical biocompatibility challenges, including nanoparticle translocation and internalization, intraocular lens opacification, leukocyte dominated responses to metallic wear debris in joint replacement, stem cell differentiation of nanostructured hydrogels, tissue responses to incontinence meshes, and restenosis of intravascular stents. Perhaps even more importantly, the identification of these molecular pathways of biocompatibility offers prospects of the control of the host response by targeting specific points in these pathways, for example the inhibition of epithelial to mesenchymal transformation that can result in excessive fibrosis, and the inhibition of activation of the NLRP3 inflammasome following exposure to biomaterial-induced stresses; this should lead to a more effective translation of biocompatibility understanding into better clinical outcomes.