The unremitting devastation created by the AIDS pandemic will probably only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where the impact of AIDS is most severe. Although formidable practical, political, economic, social, and ethical challenges face the AIDS vaccine development effort, the most fundamental challenges now reside at the level of the basic biology of HIV-1 infection and pathogenesis. Of these biological considerations, three questions loom especially large: can we design immunogens that will elicit neutralising antibodies that are reactive against a wide variety of primary HIV isolates; will vaccine-elicited cytotoxic T cells be fundamentally better at controlling HIV-1 replication and ameliorating disease progression than those responses that arise during natural HIV infection; and to what extent will the tremendous global genetic diversity of HIV-1 compromise the breadth of vaccine-elicited protective immunity and the overall effectiveness of an AIDS vaccine? Although these are three exceptionally challenging questions, they are now being approached with clear hypotheses whose testing is being facilitated by an ever-improving array of technologies for vaccine design and immunological characterisation. The extent to which the field of AIDS vaccine research can now come together to answer these questions in the best coordinated, most efficient manner will probably be an important determinant of how and when an effective AIDS vaccine will be developed.