Rational HIV vaccine design is crucially dependent on a number of factors, including a detailed understanding of the immune responses that control infection in individuals that have non-progressing disease, the impact of host genetics on these responses, and the degree of immunological cross-reactivity between the vaccine immunogen and the encountered virus antigens. Significant progress has been made in a number of these areas over the past five years, which might help in the generation of a more effective immunogen design and will provide opportunities for novel vaccine delivery options. However, the understanding of immune response(s) that can mediate protection from infection or, if infection ensues, that slow the rate of HIV disease progression is still incomplete and will require detailed studies in unprecedentedly large populations infected with different HIV clades, combining advances in virology, immunology, human host genetics and bioinformatics analyses for the optimal design of vaccine immunogens.