Around 2.5 million people become infected with human immunodeficiency virus (HIV) each year. This extraordinary toll in human life and public health worldwide will only be reversed with effective prevention. Vaccination is regarded as the most effective way to prevent infectious disease. However, there are many challenges to overcome before a successful prophylactic HIV vaccine will be available. We are participating in a global effort to develop and test candidate HIV vaccines. Two candidate prophylactic HIV vaccines that were designed and developed at the University of Cape Town (UCT) entered phase 1 clinical trials in the USA and South Africa in 2009, after a 9-year development period. In addition to the vaccines in clinical trial, there is a pipeline of candidate HIV-1 subtype C vaccines including virus-like particles, novel DNA vaccines, capripoxvirus and Bacillus Calmette-Guérin (BCG)-vectored vaccines. This article describes the history of HIV vaccine research at UCT, and the partnerships that made the project possible.