This chapter explores the central roles of tumor suppressor genes, oncogenes, and inherited cancer predisposition in regulating cell fate and maintaining genomic integrity. It highlights p53 (encoded by the TP53 gene) as a master tumor suppressor that integrates diverse stress signals to coordinate cell cycle arrest, apoptosis, senescence, DNA repair, and nonapoptotic cell death programs such as ferroptosis. Mutations in TP53, which are present in more than half of all human cancers, disable these protective mechanisms and promote malignant transformation. We contrast RB1-mediated cell cycle control with p53’s stress-responsive functions, detailing the contributions of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDKIs) to the G1-S transition. Mechanisms of tumor suppressor inactivation are explained through the classical two-hit model, haploinsufficiency, and continuum-based gene dosage effects, with PTEN serving as a prime example of dose-sensitive tumor suppressor function. We also describe tumor predisposition syndromes, which arise from germline defects affecting DNA repair pathways, chromatin regulators, or signaling networks such as RAS/MAPK. These syndromes lead to early-onset, recurrent, or tissue-specific cancers and provide insights into pathways essential for preventing oncogenesis. Finally, we emphasize emerging concepts such as somatic mosaicism, genome-first risk estimation, and the clinical implications of identifying heritable cancer risk for surveillance, targeted therapy, and family counseling.