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Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder of unknown etiology generally characterized by persistent high spiking fever, evanescent rash, and polyarthritis. The pathogenesis of AOSD is only partially known. The pivotal role of macrophage cell activation, which leads to T-helper 1 (Th1) cell cytokine activation, is now well-established in AOSD. Moreover, pro-inflammatory cytokines such as interleukin (IL)-1, -6, and -18 seem to play a key role in this disorder, giving rise to the development of new targeted therapies. For years, treatment of AOSD has been largely empirical, using nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Patients with steroid- and methotrexate-refractory AOSD can now benefit from efficient and well-tolerated biologic agents such as IL-1, IL-6, and tumor necrosis factor-α antagonists.