AbstractOne of the three key enzymes encoded by the pol gene of HIV is a Mr 32 000 protein called HIV integrase. This viral enzyme is involved in the integration of HIV DNA into host chromosomal DNA. There appears to be no functional equivalent of the enzyme in human cells. The biochemical mechanism of integration of HIV DNA into the host cell genome involves a carefully defined sequence of DNA tailoring (3′‐processing) and coupling (joining or integration) reactions. In spite of some effort in this area targeted at the discovery of therapeutically useful inhibitors of this viral enzyme, there are no drugs for HIV/AIDS in clinical use where the mechanism of action is inhibition of HIV integrase. Thus, new knowledge on inhibitors of this enzyme is of critical importance in the anti‐HIV drug discovery area. The focus of this review will be on several classes of compounds, including nucleotides, dinucleotides, oligonucleotides and miscellaneous small molecules such as heterocyclic systems, natural products, diketo acids and sulfones, that have been discovered as inhibitors of HIV integrase. Special emphasis in the review will be placed on discoveries from my laboratory on HIV integrase inhibitors that are non‐natural, nuclease‐resistant dinucleotides. Comments on future directions and the prospects for developing integrase inhibitors as therapeutic antiviral agents are discussed. Copyright © 2002 John Wiley & Sons, Ltd.