The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease. Copyright © 2011 Elsevier Ltd. All rights reserved.