HIV vaccine research is at a crossroads carefully contemplating on the next path. The unexpected results of the Merck vaccine trial, while providing a stunning blow to a field in dire need of a protective vaccine, has also raised several fundamental questions regarding the candidate immunogen itself, preexisting immunity to vaccine vectors, surrogate assays and animal models used for assessing preclinical protective responses, as well as relevant endpoints to be measured in a clinical trial. As a result, the research community is faced with the daunting task of identifying novel vaccine concepts and products to continue the search. This review highlights and addresses some of the scientific and practical concerns.