Epigenetics is a field that has swiftly gained momentum over the past few years. It has been associated with applications in development, evolution and pathogenesis. In recent studies, however, a link has surfaced that connects epigenetic changes and transplantation. From its very beginning, transplantation medicine has been confronted with the looming specter of transplant rejection. It has been shown that epigenetic changes are at least partly involved in transplant outcomes; it is therefore of great importance to further investigate the exact mechanisms affecting transplantation outcome. The use of epigenetic markers for the determination of graft prognosis and the diagnosis of transplant rejection status promises to be an efficient and accurate means in clinical applications. As will be discussed in this review, enlisting the help of epigenetic mechanisms might not only facilitate the diagnosis of graft rejection, but also contribute to attenuation of transplant rejection. This would be a very desirable aid to the field of transplant medicine.