Background: in the management of hematological malignancies, chemotherapy-induced mucositis is an increasingly recognized problem, leading to potentially severe clinical complications, treatment delays, increased costs and impairment of patients quality of life. Many forms of cytotoxic treatments given in this setting may induce several degrees of mucositis. In particular, conditioning therapy with hematopoietic stem cell transplantation (HSCT) induces a disruption of the mucosal barrier function throughout the entire gastrointestinal tract facilitating the spreading of bacteria and endotoxin with subsequent increased risk of septicemia and, in the allogeneic setting, a worsening of Graft Versus Host Disease (GVHD). Objectives: to review the role of palifermin and of other existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology in the setting of hematological malignancies. Methods: we searched for palifermin and mucositis of any region of the gastrointestinal tract using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. Results/Conclusions: The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are highly required. In this regard, palifermin (recombinant human keratinocyte growth factor) has been demonstrated to reduce the severity and the duration of oral mucositis and to significantly improve several treatment outcomes in patients submitted to autologous HSCT; data are insufficient to recommend its use in the non-autologous HSCT settings, although interesting properties of this agent deserves other investigations in order to explore other possible indications.