Advances in the prevention of graft-versus-host disease (GVHD) and opportunistic infection have improved survival after allogeneic hematopoietic cell transplantation (allo-HCT) in the past decade. However, few inroads have been made into the treatment or prevention of relapse of the underlying malignancy for which allo-HCT is being performed. The introduction of US Food and Drug Administration–approved agents with significant activity in a variety of hematologic malignancies provides an opportunity to evaluate these interventions in the allo-HCT setting. Some of the most promising new agents include tyrosine kinase inhibitors (TKIs) directed at bcr-abl, kinase inhibitors targeting fms-like tyrosine kinase 3, and immune checkpoint inhibitors blocking both CTLA4 and PD-1. Data have emerged indicating potential efficacy of these agents in preventing or treating relapse, though definitive evidence remains elusive. However, potential toxicity can be considerable, highlighting the need for further clinical trials to define the therapeutic window. This review explores the immunologic and clinical consequence of treatment with both TKIs and checkpoint inhibitors in the peri- and post–allo-HCT setting.