The specificity and power of the cellular arm of the im-mune system may provide new therapeutic approaches to cancer. With the assumption that T cells might be able to recognize and eliminate cancer cells with the same efficiency as virus-infected cells, investigators have searched many years for ways to trigger or amplify the patient’s inadequate immune response to tumors. Much attention has been given to the role of CD8+ CTLs because most tumors are MHC class I positive, but negative for MHC class II. Moreover, CD8+ CTLs are able to lyse tumor cells directly upon recognition of peptide–MHC class I complexes expressed by the tumor, and their ability to eradicate large tumor masses in vivo has been demonstrated. The focus in cancer immunology on CD8+ T cell responses is also exemplified by an increasing list of tumor antigens identified by tumor-reactive CD8+ CTLs. CD4+ Th cells have received far less attention, which is remarkable given the pivotal role of these cells in regulating most antigen-specific immune responses. Until now, only a few Th epitopes derived from human tumor antigens recognized by CD4+ Th cells have been identified (1, 2). Three studies published in this issue describe the identification of melanoma antigens that are recognized by CD4+ T cells in the context of MHC class II molecules (3–5). Charting the Th response against human melanoma as well as other tumors is important for the development of optimal anticancer vaccines and for the design of other T cell–related therapeutic modalities in cancer.