Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17–32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.