Adult-onset Still's disease (AOSD) is a rare systemic auto-inflammatory disorder (SAID). Although the pathogenesis of the disease is complex and far from being fully understood, recent progresses in pathophysiological knowledge have paved the way to new diagnostic approaches. Indeed, AOSD diagnosis can be a real challenge, owing to its infrequency, and to the lack of specificity of the principal clinical features (high fever, arthralgia or arthritis, skin rash) and laboratory findings (elevated acute phase reactants, hyperleukocytosis ≥ 10,000 cells/mm3 with neutrophils ≥80%). None of these manifestations is disease-specific, so clinicians must first rule out neoplastic, infectious or inflammatory conditions. Besides these diagnostic difficulties, several other challenges remain. AOSD is very heterogeneous in terms of clinical presentation, evolution and severity. Thus, new biomarkers are required to assess: (i) disease activity; (ii) disease severity (through the identification of patients at risk of severe organ failure, and eventually of life-threatening complications, such as reactive haemophagocytic lymphohistiocytosis); (iii) disease evolution (which can be monophasic, relapsing, or progressive, with either systemic inflammation or chronic erosive arthritis); (iv) and treatment efficacy. The identification of new markers can only be done through a better understanding of the pathogenesis of the disease. After a short focus on the current AOSD pathophysiological knowledge, this article reviews the main biomarkers that have been proposed in the literature over the last few years.