Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) play key roles in initiating innate and adaptive immune responses. Based mainly on animal studies there is growing evidence to suggest that TLRs are involved in the development of chemotherapy-induced mucositis and in the propagation of graft versus host reactions as well as graft versus tumor effects in allogeneic hematopoietic stem cell transplantation (HSCT). In this review we discuss these findings along with the emerging, although still preliminary, clinical evidence, that points to a role of PRRs in determining the outcome of HSCT and new therapeutic perspectives that may be related to this development.