Haploidentical related donors are an attractive alternative source of stem cells for allogeneic stem cell transplantation due to widespread availability and ease of stem cell procurement. Historically, haploidentical stem cell transplantation (HaploSCT) with extensive T-cell depletion has been associated with high rates of infectious complications and nonrelapse mortality (NRM). Post-transplantation cyclophosphamide (PTCy) has been shown to induce immune tolerance, effectively control graft-versus-host-disease (GVHD), and is associated with lower NRM, making it a preferred option for patients undergoing HaploSCT. Over the last decade, several groups investigated PTCy for GVHD prevention in HaploSCT; it is now successfully utilized with both myeloablative and nonmyeloablative conditioning regimens with survival comparable to HLA-matched transplantation. Future directions will focus on optimizing conditioning regimens by diagnosis, improving donor selection, and enhancing graft-versus-leukemia effect.