Mast cells (MC) play an important role in the defense against microbial agents, parasites and venoms. The term mastocytosis encompasses a group of diseases characterized by abnormal MC accumulation, divided into cutaneous and systemic forms. The diagnosis of indolent systemic mastocytosis (ISM) is supported by the presence of MC clusters in bone marrow and/or extracutaneous organs, elevated serum tryptase levels, altered expression of MC surface markers, and presence of an activating c-KIT mutation. Patients with ISM carry an increased risk of severe anaphylaxis, particularly to hymenoptera stings. Management of ISM includes symptomatic treatment, avoidance of triggering factors, desensitization and off-label omalizumab. Novel tyrosine kinase inhibitors targeting the mutated c-KIT are promising in refractory ISM and advanced mastocytosis.