Tumor suppressor genes encode for proteins whose normal function is to inhibit cell transformation and whose inactivation is advantageous for tumor cell growth and survival. A variety of mechanisms result in the inactivation of tumor suppressor genes, including intragenic mutations, chromosomal deletions, and loss of expression by methylation-mediated transcriptional silencing or increased proteolysis. Tumor suppressor genes participate in a variety of critical and highly conserved cell functions, including regulation of the cell cycle and apoptosis, differentiation, surveillance of genomic integrity and repair of DNA errors, signal transduction, and cell adhesion. Tumor suppressor functions can be separated into 2 major categories: gatekeepers and caretakers. Gatekeepers directly inhibit tumor growth or promote tumor death. Inactivation of these genes contributes directly to cancer formation and progression. Among them, the p53 gene is the most well known. Located on chromosome band 17p13, p53 encodes a 53-kd multifunctional transcription factor that regulates the expression of genes involved in cell cycle control, apoptosis, DNA repair, and angiogenesis. In breast cancer, most studies have shown that p53 mutation or down-regulation is associated with adverse prognosis. Other tumor suppressor genes of interest in breast cancer include the retinoblastoma gene (pRb), PTEN, p16, nm23, and maspin.