The molecular identification and characterization of antigenic epitopes recognized by T cells on human cancers has rapidly evolved since the cloning in 1991 of MAGEA1, the first gene reported to encode a CTL-defined human tumor antigen. In the expanding field of human tumor immunology, unique tumor antigens constitute a growing class of T cell–defined epitopes that exhibit strong immunogenicity. Some of these antigens, which often derive from mutation of genes that have relevant biological functions, are less susceptible to immunoselection and may be retained even in advanced tumors. Immunogenicity and constitutive expression of the unique tumor antigens provide a strong rationale for the design of novel, patient-tailored therapies that target such determinants. Here we discuss the immunologic relevance of unique tumor antigens in the light of the prospects for exploiting such epitopes as targets for patient-specific immune intervention strategies.