During the decade 1987-1996, the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) provided infrastructure support for both intramural and extramural anti-HIV (human immunodeficiency virus) drug discovery research and development. This retrospective review describes some of the anti-HIV lead discovery and development that took place under DTP auspices or which was substantially facilitated by resources made available through the DTP. Examples highlighted include leads identified through the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts, and these are classified according to the mechanism of action targeting the critical steps within the replication cycle of HIV.