Disease relapse is the leading cause of failure for patients with hematological malignancies who have received allogeneic hematopoietic cell transplantation (HCT). Maintenance therapy administered after HCT is a promising strategy to reduce the incidence of relapse and enhance the curative potential of HCT. Historically, maintenance therapy was not possible due to off-target toxicities from conventional chemotherapy. With the advent of specifically targeted agents—such as those targeting BCR-ABL, FLT3, IDH1, IDH2 and Menin—therapy given in the immediate period after HCT while patients remain in remission has become a reality. Research investigations and clinical applications of this approach have greatly increased in recent years, with a rapidly expanding number of available therapeutic agents waiting to be tested in the post-transplant setting. However, many questions and challenges remain regarding the feasibility and clinical impact of maintenance therapy after HCT. In this chapter, we review the published data as well as ongoing studies regarding the rapidly evolving field of maintenance therapy after HCT.