Research in the laboratory is aimed at uncovering the mechanisms of cell death by the p53 and p14ARF tumor suppressor proteins. The p53 tumor suppressor protein continues to be distinguished as the most frequently mutated gene in human cancer. Indeed, along with p53’s negative regulator p14ARF (ARF), this tumor suppressor pathway is likely to be mutated in 100% of all cancers. Whereas many of the mechanisms whereby p53 and ARF accomplish their function as tumor suppressors are known, a great deal remains undiscovered. For example, following an apoptotic stimulus, we and others have shown that a fraction of p53 localizes to mitochondria, and there-in acts directly with BCL2 family members to induce programmed cell death. However, it is not clear how trafficking of p53 to mitochondria is regulated, or whether p53 interacts with other mitochondrial proteins in order to induce cell death. Additionally, the contribution of this direct mitochondrial pathway to p53-dependent cell death overall has not yet been determined. These questions are active areas of investigation in the laboratory. We have found that a polymorphism at codon 72 in p53 significantly influences the ability of this protein to localize to mitochondria, and also to induce programmed cell death. Along with our colleague Monica Hollstein (German Cancer Research Foundation), we have created the first mouse model for the codon 72 polymorphism of p53. We are using this reagent to define the contribution of this polymorphism, and mitochondrial p53, to tumor suppression, cancer risk, and the efficacy of therapy. We have recently begun using 2-dimensional gels and mass spectrometry to identify other proteins specific to the mitochondria of dying cells. These studies have allowed us to identify the tumor suppressor protein p14ARF as a mitochondrially-localized protein. Interestingly, we find that mitochondrial localization of ARF does not result in apoptosis. Rather, our data indicate that the p14ARF tumor suppressor induces an alternate form of cell death, termed autophagy. The broad, long-term objective of research in the laboratory is to elucidate the mechanisms of cell death and tumor suppression for the two most commonly mutated genes in human cancer, p53 and p14ARF. A natural corollary of this goal is to elucidate the contribution of the codon 72 polymorphism of p53 to cancer risk.