Graft-versus-host disease (GvHD) is a frequent cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (alloHCT) and optimal approaches for its prevention have been recently updated. Post-transplant cyclophosphamide (PTCy) has demonstrated impressive results in the setting of haploidentical donor transplantation, allowing for a more widespread application of alloHCT. For this reason, over the years, several groups have implemented the use of PTCy in the context of transplantation from HLA-matched related and unrelated donors, as a replacement for standard GvHD prophylaxis based on calcineurin inhibitors and methotrexate. With increasing results from retrospective studies and new insights from prospective clinical trials, this comprehensive reevaluation of the literature aims to clarify the precise role of PTCy in this context. This review will summarize and critically discuss the overall results of the use of PTCy in alloHCT from HLA-matched donors, unmet needs, and future perspectives.