In recent years, there have been reports of immunotherapy inducing objective clinical responses in limited numbers of cancer patients. More frequently, however, clinical responses are not observed. Understanding the immunological mechanisms underlying successful immunotherapy are crucial if the field is to move forward. In the article under evaluation, Coulie et al. examine the T-cell receptor repertoire in a melanoma patient showing durable remission after MAGE-specific immunotherapy. The paper provides convincing evidence that the phenomenon of epitope spreading is critical to the development of effective antitumor immunity.