Mast cell activation diseases are common as either atopic diseases or rarely occur as mastocytosis and mast cell activation syndrome. Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, particularly the skin and bone marrow. Mast cell activation syndrome is characterized by systemic symptoms ranging from flushing and abdominal cramps to anaphylaxis secondary to mast cell degranulation. The aim of this review was to increase the awareness of the clinical features, classification, diagnosis, and treatment approaches of systemic mastocytosis. In addition, the role of mast cell activation syndrome in the differential diagnosis will be discussed.