The identification of tumor antigens recognized by T cells led to the design of therapeutic strategies aimed at eliciting adaptive immune responses. The last decade of experience has shown that, although active immunization can induce enhancement of anticancer T-cell precursors (easily detectable in standard assays), most often they are unable to induce tumor regression and, consequently, have scarcely any impact on overall survival. Moreover, in the few occasions when tumor rejection occurs, the mechanisms determining this phenomenon remain poorly understood, and data derived from in vivo human observations are rare. The advent of high-throughput gene-expression analysis (microarrays) has cast new light on unrecognized mechanisms that are now deemed to be central for the development of efficient immune-mediated tumor rejection. The aim of this article is to review the data on the molecular signature associated with this process. We believe that the description of how the mechanism of immune-mediated tissue destruction occurs would contribute to our understanding of why it happens, thereby allowing us to develop more effective immune therapeutic strategies.