For patients with hematologic malignancies, allogeneic hematopoietic cell transplantation (alloHCT) offers a potential curative treatment option, primarily due to an allogeneic immune response against recipient tumor cells (ie, graft-versus-leukemia [GVL] activity). However, many recipients of alloHCT develop graft-versus-host disease (GVHD), in which allogeneic immune responses lead to the damage of healthy tissue. GVHD is a leading cause of nonrelapse mortality and a key contributor to morbidity among patients undergoing alloHCT. Therefore, improving alloHCT outcomes will require treatment strategies that prevent or mitigate GVHD without disrupting GVL activity. Janus kinases (JAKs) are intracellular signaling molecules that are well positioned to regulate GVHD. A variety of cytokines that signal through the JAK signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis, including dendritic cells, macrophages, T cells, B cells, and neutrophils. Importantly, despite JAK regulation of GVHD, preclinical evidence suggests that JAK inhibition preserves GVL activity. Here we provide an overview of potential roles for JAK signaling in the pathogenesis of acute and chronic GVHD as well as effects on GVL activity. We also review preclinical and clinical results with JAK inhibitors in acute and chronic GVHD settings, with added focus on those actively being evaluated in patients with acute and chronic GVHD.