The monocyte-derived macrophage is recognized as a critical determinant in biocompatibility, but its appearance in the chronic inflammatory phase is accompanied by the presence of lymphocytes, which have been much less studied in this regard. Here, we first present an overview of the physiologic continuum comprising host reactions to the surgical implantation of biomaterial. Secondly, we describe our collective research efforts, which indicate that lymphocytes are additional and key cellular determinants of biocompatible outcome. Thus, bioengineering advances will require that lymphocyte responses be regarded as integral components of innate inflammatory and immune/immunotoxic cell interactions at sites of biomaterial implantation.