Epigenetics refers to heritable modifications of the genome that are not a result of changes in the DNA sequence and result in phenotypic changes. These changes can be stably transmitted through cell division and are potentially reversible. Epigenetic events are very important during normal development wherein a single progenitor cell proliferates and differentiates into various somatic cell types. This process occurs through modification of the genome without changing the genetic code. Because epigenetic control of gene expression is so important, aberrant epigenetic regulation can lead to disease and cancer. This article reviews epigenetic changes seen in cancer by examining epigenetic changes commonly found in multiple myeloma, a common hematologic malignancy of plasma cells. Epigenetic control of gene expression can be exerted by changes in DNA methylation, histone modifications, and expression of noncoding RNAs. Each of these regulatory mechanisms interacts with the others at different genomic locations and can be measured quantitatively within the cell, requiring that we consider these mechanisms not individually but as a biological system. DNA methylation was the earliest discovered epigenetic regulator and has been the focus of most investigations in cancer. We have thus focused on DNA methylation changes in the pathogenesis of multiple myeloma, which promises to become an excellent model for systems biological studies of epigenomic dysregulation in human disease.