AbstractHIV‐1 integrase is a protein of Mr 32 000 encoded at the 3′‐end of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3′‐processing (3′P)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.g., T‐cell) by HIV. Unlike major successes seen in the development of clinically approved anti‐HIV agents against HIV reverse transcriptase and HIV protease, there are no FDA‐approved anti‐HIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase. This review summarises some key advances in the area of integrase inhibitors with the major focus being on new generation inhibitors. Special emphasis is placed on diketo acids with aromatic and heteroaromatic moieties, diketo acids with nucleobase scaffolds, bis‐diketo acids, functionalised naphthyridines and other isosteres of diketo acids. Data pertaining to integrase inhibition and in vitro anti‐HIV activity are discussed. Mention is made of drugs in clinical trials, both past (S‐1360, L‐870,810 and L‐870,812 and present (GS‐9137 and MK‐0518). Other promising drugs, including those from the authors' laboratory, are referred. Resistant mutants arising from key integrase inhibitors and cross‐resistance are indicated. Copyright © 2007 John Wiley & Sons, Ltd.