Noninvasive molecular imaging of acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation has great potential to detect GvHD at the early stages, aid in grading of the disease, monitor treatment response, and guide therapeutic decisions. Although the specificity of currently available tracers appears insufficient for clinical GvHD diagnosis, recently, several preclinical studies have identified promising new imaging agents targeting one or more biologic processes involved in GvHD pathogenesis, ranging from T-cell activation to tissue damage. In this review, we summarize the different approaches reported to date for noninvasive detection of GvHD using molecular imaging with a specific focus on the use of PET. We discuss possible applications of molecular imaging for the detection of GvHD in the clinical setting, as well as some of the predictable challenges that are faced during clinical translation of these approaches.