Human genetic variation comprises millions of common and rare variants, most of which are functionally neutral. Rare high-penetrance mutations and numerous low-penetrance variants collectively shape susceptibility to complex diseases, including cancer. While monogenic disorders arise from single pathogenic variants, most cancers follow a polygenic architecture influenced by dozens to hundreds of alleles interacting with environmental and lifestyle factors. Genome-wide association studies (GWAS) have identified many loci associated with cancer risk, yet common variants explain only a small fraction of heritability. In contrast, germline mutations in tumor-suppressor genes such as BRCA1/BRCA2, TP53, RB1, and APC confer very high cancer risks. Advances in next-generation sequencing have enabled routine whole genome sequencing, allowing comprehensive detection of somatic mutations, structural variants, epimutations, and mutational signatures. Whole genome sequencing informs prevention, diagnosis, risk stratification, and therapy selection by revealing driver mutations, inherited predisposition alleles, and genomic instability processes such as hypoxia-driven DNA repair deficiency. Large-scale initiatives including TCGA, ICGC, PCAWG, and national genome programs have catalogued hundreds of cancer driver genes and uncovered catastrophic events such as chromothripsis and kataegis. Integrating genomic, transcriptomic, and epigenomic information is transforming cancer classification and supports precision oncology grounded in molecular mechanisms.