Oncogenesis results from a progressive accumulation of genetic aberrations consequent to a complex interplay between carcinogenic factors and innate infidelity of DNA surveillance mechanisms. Although the development of genetic aberrations is random, those conferring survival advantages are selected for in a Darwinian manner, thus allowing continuous adaptation to selection pressures. Chromosomal aberrations are a prominent manifestation of genetic damage, which can be closely linked with tumor behavior and outcome as exemplified by curative treatment of chronic myelogenous leukemia resulting from targeting the BCR-ABL translocation. In the case of head and neck squamous cell carcinomas (HNSCC), chromosomal changes are detectable at all stages of tumor development, providing excellent opportunities for genomic prognostication and therapy. Several studies have shown that the overall genomic profile of HNSCC is highly consistent, but individual tumors vary significantly in their complement of genetic alterations, thereby confounding clinical correlation. The application of modern genetic and bioinformatic analytic approaches has facilitated the identification of critical genomic changes in HNSCC, many of which have been linked to clinical outcome. These genetic aberrations represent excellent targets for novel therapeutics, but require validation. The initiation of phase III trials evaluating the therapeutic utility of genetic aberrations suggests a promising future for genome-based treatment of HNSCC.