Familial Mediterranean fever (FMF) is an autosomal, recessively inherited disease, affecting people of Jewish, Arabic, Turkish and Armenian ancestry. The disease is the prototype of the periodic febrile syndromes. Its hallmark is short attacks of fever and painful manifestations in the abdomen, joints, chest, scrotum and skin. Chronic and protracted manifestations, particularly nephropathic amyloidosis, chronic arthritis, and protracted myalgia, may also occur in the disease. The diagnosis of FMF should be considered in individuals of an appropriate ethnic background who present with febrile disease of episodic nature. The differential diagnosis in this case is broad and includes a large number of infectious, inflammatory and genetic diseases. However, in most cases, the very specific general and site-restricted features of the FMF attacks on the one hand, and the absence of manifestations typical of other conditions on the other hand, determine the diagnosis of FMF. This chapter presents clues and tips that help in the diagnosis and treatment of FMF.