The rapid replication of HIV-1 and the errors made during viral replication, cause the virus to evolve rapidly in patients, making the problems of vaccine development and drug therapy particularly challenging. In the absence of an effective vaccine, drugs are the only useful treatment. Anti-HIV drugs work; so far drug therapy has saved more than three million years of life. Unfortunately, HIV-1 develops resistance to all of the available drugs. Although a number of useful anti-HIV drugs have been approved for use in patients, the problems associated with drug toxicity and the development of resistance means that the search for new drugs is an ongoing process. The three viral enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR) are all good drug targets. Two distinct types of RT inhibitors, both of which block the polymerase activity of RT, have been approved to treat HIV-1 infections, nucleoside analogs (NRTIs) and nonnucleosides (NNRTIs), and there are promising leads for compounds that either block the RNase H activity or block the polymerase in other ways. A better understanding of the structure and function(s) of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular drugs that are effective against the current drug-resistant strains of HIV-1.In the absence of an effective vaccine, drugs are the only therapeutic tools that can be used to treat HIV-1 infections. Unfortunately, HIV-1 infections cannot be cured, so that drug therapy, once initiated, must be continued for the life of the patient. This places a special burden on the design of anti-HIV drugs: They need to be relatively nontoxic so that they can be used in longterm therapy. HIV-1 replication is error prone (1) (and references within) and the errors that arise during the viral life cycle, together with the rapid replication of the virus in patients, allows the virus to escape the host's immune system and develop resistance to all of the available drugs (2). The virus evolves sufficiently rapidly that, unless the therapy is well-© 2008 Elsevier Ltd. All rights reserved.Correspondence: Professor Eddy Arnold, Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854-5627, USA, Email: arnold@cabm.rutgers.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. designed, resistance will develop in all treated patients. The only way to stop the development of resistance is to completely block viral replication; this, in turn, stops the evolution of resistance. It takes ...