There has been a rush to convert discovery of new melanoma antigens into cancer vaccines for the therapy of melanoma. The result has been disappointing from a clinical standpoint. The premise behind rapid pursuit of peptide vaccines for melanoma therapy was that the spontaneous tumor-associated immune response was too weak to be effective. However, it is increasingly clear that the host-tumor relationship is a complex interplay of immune response, immune escape, and immune adaptation, with multiple layers of regulatory control and modulation of responses over time. The lesion in the immune response to cancer is much more complex than simply a weak immune response to defined antigens. Current results should serve as a call to take a closer look at immune regulatory processes and principles and to develop more comprehensive and multiagent approaches to modulate the host-tumor relationship. Development of effective immune therapy for cancer will require (a) more comprehensive and real-time immune monitoring in various tissue compartments and (b) patient-specific modulation of immune responses, informed by the real-time monitoring. Peptide antigens associated with MHC class I or class II molecules are the molecular targets for T-cell recognition of cancer. To characterize the host-tumor relationship and to optimize cancer vaccines, clinical studies using defined peptide antigens offer special opportunities to advance the field and thus have an important place in the ongoing development of effective immune therapy of melanoma.