In recent years, exciting developments in the understanding of the multi-step HIV-1 entry process have revealed potential approaches for therapeutic intervention that will compensate for the early disappointments of the soluble CD4 antigen approach. Although details of the HIV-1 fusion process are clearly complex, the proof-of-concept in the clinic provided by T-20 gives high hopes that new generation inhibitors of HIV fusion will be developed. This review highlights novel drug discovery technologies that are being employed in the search for such inhibitors.