Several groundbreaking trials and over 1 million years of patient experience have established tenofovir as an important component of HIV treatment. Tenofovir has demonstrated potent antiviral efficacy, with a low risk of developing resistance when used as part of an effective combination regimen. It is generally well tolerated, with a low risk of lipoatrophy and a favourable effect on lipid profile compared with older nucleoside analogue agents such as stavudine or zidovudine. Clinical data suggest that switching from thymidine analogues to a tenofovir-containing regimen can benefit patients with lipid abnormalities or lipoatrophy. This article reviews the development of tenofovir, including pivotal studies that have influenced HIV clinical practice.