Familial Mediterranean Fever (FMF) is a rare autosomal recessive autoinflammatory disorder involving the innate immunity and affecting almost exclusively populations with Mediterranean origin. Clinical features include recurrent episodes of fever, leukocitosis, serositis (peritonitis or pleuritis, arthritis), myalgia or erysipelas-like skin lesions, lasting 12-72 hrs. The MEFV gene mutations on chromosome 16p13.3 encodes the abnormal pyrin (marenostrin), a protein expressed in granulocytes, monocytes, serosal and synovial fibroblasts and involved in the activation of caspase-1 and the processing and release of active pro-inflammatory IL-1β. Since the first report in 1972, maintenance therapy with colchicine, a tricyclic neutral alkaloid, remains the mainstay of treatment in symptomatic FMF patients since it reduces the disease activity and prevents the development of secondary amyloidosis and renal damage. Adjunctive symptomatic therapy to colchicine includes nonsteroideal antinflammatory drugs and corticosteroids. In a small group of colchicine-intolerant or colchicine-resistant FMF patients, alternative treatments must be considered. Evolving experiences have focussed on the potential effectiveness of biologic agents working as TNF-α inhibitors (etanercept, infliximab), IL-1 trap (Rilonacept), IL-1 inhibitors (Anakinra, Canakinumab) and IL-6 receptor antibody (Tocilizumab). Interferon-α and thalidomide have also been employed in FMF patients. Still, clinical trials are mainly uncontrolled and restricted to few cases, thus requiring definitive conclusions. Old, and new treatments are discussed in the rare FMF disease, with the concept that any ideal treatment has to stand the test of time.