Patients with advanced melanoma can survive longer after treatment with the immunotherapy drug ipilimumab. Kvistborg et al. show how this therapeutic antibody exerts its beneficial effects. Although directed against an immune inhibitor, the drug unexpectedly failed to increase the magnitude of immune T cell responses. Rather, the patients’ T cells targeted a greater variety of antigens. This increased breadth of the T cell response suggests that ipilimumab works by activating T cells directed against previously untargeted tumor-related antigens, rather than by boosting preexisting immune responses. If so, similar strategies could be successful in battling other cancers….