The long-term stability of prosthetic implants is ultimately a function of the integrity of the biologic interaction between the resident tissues and cells and the biomaterial. Connective tissues of the skeleton undergo constant remodeling and turnover, and the interface with the implant biomaterial is therefore a dynamic structure that results from ongoing differentiation of progenitor cells into functional cellular phenotypes. An understanding of the regulation of the mechanisms by which progenitor cells initiate and maintain their interactions with the biomaterial surface while undergoing the necessary differentiation processes is thus essential to optimizing the long-term stability of prosthetic implants. This review presents evidence that the interactions between adult mesenchymal stem cells, as the principal progenitor cell type of skeletal connective tissues, and the biomaterial surfaces are influenced by surface chemistry and topography and regulated by the extracellular matrix and growth factors. Mesenchymal stem cells are also the targets of the wear debris particles that are a by-product of implant biomaterials, resulting in direct and microenvironmental effects, including apoptosis, suppression of proliferation and osteogenic differentiation, and the production of proinflammatory cytokines, that compromise the long-term stability of the bone-implant interface. These effects are initiated by endocytosis of the submicron particles by the mesenchymal stem cells. These observations strongly suggest that optimization of the stability of implant osseointegration must address factors that enhance and promote the biologic activities of the stem/progenitor cells of skeletal connective tissues.