The increasing complexity of biomedical research is leading to the exploration of new models for large-scale collaborative research. This Big Science approach, however, has created anxieties and potential tensions between investigator-driven research, and research guided by a more organized, collaborative effort. Another potential tension exists between research conducted purely in search of new knowledge and research aimed at finding solutions. We argue that big biomedicine--the work of coordinated multidisciplinary groups that use the latest technologies to solve complex problems--can be an important way to harness the creativity of individual investigators, stimulate innovation, and supply the infrastructure, experimental systems, and resources needed to solve the urgent health problems confronted by our global society. We discuss this using the example of the Global HIV Vaccine Enterprise.