The integrin alphavbeta3 is thought to play a key role in the initiation and/or progression of several human diseases, including osteoporosis, restenosis following percutaneous transluminal coronary angioplasty (PTCA), rheumatoid arthritis, cancer and ocular diseases. Antagonism of integrin alphavbeta3 is therefore expected to provide an approach for the treatment and/or prevention of these diseases. A variety of potent, small-molecule alphavbeta3 antagonists have been identified, several of which are active in disease models, thereby demonstrating the therapeutic potential of alphavbeta3 antagonism. This review will focus on recent advances in the identification of small-molecule alphavbeta3 antagonists, with an emphasis on those studies where small-molecule alphavbeta3 antagonists have been used in proof-of-concept studies in vivo.