The retroviral RT is properly under intensive study as the major target of antiviral therapy. The enzyme exhibits a number of features that make it an attractive target: it is crucial for viral replication; its RNA-dependent DNA polymerase activity is probably unique to viral replication, or if not unique, is generally unimportant in host cell function; its activities are readily monitored; and powerful lead compounds in the form of nucleotide analogues are already in hand. Our laboratory has been involved in studies to elucidate the structure and function of the HIV-1 RT and to develop a formal genetics of the enzyme. Working with constructs expressing RT in bacteria, we been able to use in vitro mutagenesis to localize functions on the molecule; by coupling mutagenesis with high-throughput screening of colonies, we have been able to isolate mutants with specific, rare, phenotypes. We believe that extensions of these efforts will help us to understand the functions of the protein and, coupled to a detailed three-dimensional structure, should facilitate the development of new and better inhibitors.