Mucosal barrier injury (MBI), also known as mucositis, is the result of the cytotoxic effects of many treatments given for hematological malignancies (HMs) and represents a major source of potentially devastating clinical complications and negative consequences afflicting the patient's management, such as a longer hospitalization, the need of analgesic and total parenteral nutrition use, and increased costs. The available measures for the prevention and treatment of MBI have been substantially limited to the control of pain, infection, bleeding and nutrition. However, in the last decade, a better insight into the complex pathogenesis of MBI has led to the development of novel therapeutic options, such as palifermin, which has been one of the major breakthroughs in the management of this condition, potentially allowing a targeted approach to MBI. Nevertheless, and despite these significant advances, MBI still remains a significant clinical problem in the management of HM and an important burden of sufferance for afflicted patients.