Macrophage activation syndrome (MAS) is an infrequent but potentially life-threatening complication of various autoimmune diseases. It is characterized by excessive activation of macrophages induced by a dysfunction of the immune system, although the underlying abnormalities remain to be delineated. Sepsis-like symptoms accompanied by cytopenia, hepatosplenomegaly, coagulopathy and multiple organ dysfunctions are typical disease manifestations. Due to the lack of validated classification criteria and distinct laboratory markers, the diagnosis of MAS is often difficult to establish. However, early diagnosis and therapy is of utmost importance to ensure best possible outcome. Treatment regimens include high doses of glucocorticoids, classical immunosuppressive agents as well as novel biologics.