Cancer is frequently called a genetic disease. What is often overlooked are the epigenetic contributions to malignancies. Evidence exists that epigenetic changes precede genetic mutations in many cancers. Most often in the cancers examined to date, epigenetic abnormalities, or epimutations, greatly exceed sequence mutations in frequency. While mutations affect the genetic sequence, the hardware of the genetic code, epigenetic marks select genes and chromosomal regions for transcriptional activity, acting as the software that selects and interprets the code to determine cell phenotype. Epigenetic changes may even lead directly to large mutational events like translocations and contribute to selection of splice variants of expressed genes. In this lecture, residents will be taught the general forms of epigenetic changes that are known to contribute to gene expression, phenotype, and the malignant condition. Fundamental concepts will be presented and will be supported by published research describing human cancers to illustrate classic principles. Epigenetic research in veterinary cancers will be presented to paint our current understanding of these principles in companion animal cancers.