Allogeneic haemopoietic stem cell transplantation (HSCT) is increasingly used to treat haematological malignant diseases via the graft-versus-leukaemia (GvL) or graft-versus-tumour effects. Although improvements in infectious disease prophylaxis, immunosuppressive treatments, supportive care, and molecular based tissue typing have contributed to enhanced outcomes, acute graft-versus-host disease and other transplant related complications still contribute to high mortality and significantly limit the more widespread use of HSCT. Sphingosine 1-phosphate (S1P) is a zwitterionic lysophospholipid that has been implicated as a crucial signaling regulator in many physiological and pathophysiological processes including multiple cell types such as macrophages, dendritic cells, T cells, T regulatory cells and endothelial cells. Recent data suggested important roles for S1P signaling in engraftment, graft-versus-host disease (GvHD), GvL and other processes that occur during and after HSCT. Based on such data, pharmacological intervention via S1P modulation may have the potential to improve patient outcome by regulating GvHD and enhancing engraftment while permitting effective GvL.