Summary Since the Human Immunodeficiency Virus was first isolated in 1983, we have come to know it in exquisite detail. Yet we still do not understand sufficiently how it causes disease. Neither do we know why chimpanzees and some African monkeys, which are the natural reservoir of the precursors of HIV-1 and HIV-2, can harbour similar levels of virus without becoming ill. Our knowledge of the replication cycle of HIV as a retrovirus has been pivotal in the development of antiviral drugs. Our knowledge of the cellular tropism and cell surface receptors exploited by the virus help to explain the pattern of immune deficiency, wasting and dementia that make up the clinical dimensions of AIDS. The extraordinary rate of genetic and phenotypic evolution of the virus – both within the infected individual and across the worldwide pandemic – partially explains why no vaccine constructs to date have been successful. HIV comprises just 9 genes but represents one of humanity's most formidable foes.