Approximately 50% of all human malignancies exhibit mutation and aberrant expression of p53, making this protein an interesting candidate target for immunotherapy of cancer. Mutations in p53 are highly diverse. Therefore, targeting of determinants within the wild-type p53 sequence appears most practical. Despite the fact that p53 is ubiquitously expressed, adoptive immunotherapy of tumor-bearing mice with p53-specific cytotoxic T lymphocytes (CTL) results in eradication of p53-overexpressing tumors in the absence of immunopathological damage to normal tissues. These CTL also eliminate tumors that do not show greatly enhanced expression of p53, indicating that the sensitivity of these tumors for p53-specific CTL is determined by the efficiency by which p53-derived peptides are processed into class I MHC, rather than by the steady state levels of p53. Of note, although p53-specific CTL can readily be isolated from p53-/- mice, tolerance for this self antigen may prevent induction of similarly effective CTL in p53+/+ subjects. The T helper (Th) branch of the p53-specific immune response does not seem to be profoundly affected by tolerance. In addition, more and more evidence is obtained for the pivotal role of tumor-specific Th cells in the induction and effector phases of the antitumor response, also against tumors that lack class II MHC expression. The efficacy of Th cells, specific for a recently identified class II MHC-restricted p53 peptide, against p53-overexpressing tumors is currently being investigated. In addition, natural and induced Th responses are analyzed both in a murine tumor model and in a phase I clinical trial involving p53-specific vaccination of colon cancer patients.