Epigenomic modifiers, such as histone deacetylase inhibitors, are compounds that regulate gene expression by interfering with the enzymatic machinery that maintains the proper chromatin structure of the nucleus. These compounds are at the forefront of novel therapeutic agents for the treatment of several diseases including cancer and genetic disorders such as beta-thalassemia and sickle cell disease. Here we review the current understanding of the mechanism of action of epigenomic modifiers in the treatment of beta-thalassemia and sickle cell anemia. We also discuss how the lessons learned from the study of the effects of these compounds on the beta-globin locus, one of the best characterized regions of the human genome, might contribute to the understanding of the mechanism of action of these same compounds in cancer, where the specific regions of the genome that are responsible for the pathophysiology of the disease are often poorly defined.