Mucosal barrier injury (mucositis) is a common complication of many treatments used in hematologic malignancies, affecting most patients whose neoplasms are treated with intensive chemotherapy, and virtually all those receiving myeloablative conditioning regimens prior to hematopoietic stem cell transplantation. Mucositis has been identified as a critical risk factor for infections and is a major driver of analgesic and total parenteral nutrition use. Patients with this complication require careful analgesic therapy, additional nursing care and longer hospitalization. To date, the measures to prevent and treat this potentially devastating complication are inadequate and limited to the control of pain, infections, bleeding and nutrition. Nevertheless, in the last decade, a better insight into the pathogenesis of the mucosal damage has led to the development of novel therapeutic options which potentially could allow a targeted approach to mucositis.