Limited osseointegration of current orthopedic biomaterials contributes to the failure of implants such as arthroplasties, bone screws, and bone grafts, which present a large socioeconomic cost within the United States. These implant failures underscore the need for biomimetic approaches that modulate host cell–implant material responses to enhance implant osseointegration and bone formation. Bioinspired strategies have included functionalizing implants with extracellular matrix (ECM) proteins or ECM-derived peptides or protein fragments, which engage integrins and direct osteoblast adhesion and differentiation. This review discusses (1) bone ECM composition and key integrins implicated in osteogenic differentiation, (2) the use of implants functionalized with ECM–mimetic peptides/protein fragments, and (3) growth factor–derived peptides to promote the mechanical fixation of implants to bone and to enhance bone healing within large defects. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2010.