© 2017 Informa UK Limited, trading as Taylor & Francis Group. Introduction: Post transplant cyclophosphamide (PT/Cy) in association to other immunosuppressive agents or alone has emerged as a promising pharmacological strategy in the setting of allogeneic hematopoietic cell transplant (allo-HCT). Its safety profile and effectiveness in reducing GvHD (acute GvHD incidence comprised between 15 and 30%, chronic GvHD 20–30% in the haploidentical setting) contributed to the spreading of this technique all o ver the world. Areas covered: This review summarizes the use of PT/Cy in the setting of allo-HCT, both for oncological and non-malignant hematological diseases. Recent studies showed the feasibility of more intense conditioning regimens instead of the original NMAC. The use of peripheral blood stem cells instead of bone marrow as graft source (slightly increase of acute GvHD grade 2 but no differences in survival outcomes) was another significant variation to the original protocol. Later on, PT/Cy alone or in combination with other immunosuppressive agents (ATG, sirolimus, cyclosporine) were tested in the HLA-matched donor setting where lower GvHD rates are reported (acute GvHD grade 3 of 5–10% and chronic GvHD of 10–20%) Expert commentary: The best graft source and type of donor is still ongoing. Moreover, the research of the best pharmacological partner of PT/Cy remains an open question. © 2017 Informa UK Limited, trading as Taylor & Francis Group.