Systemic onset juvenile idiopathic arthritis is a chronic inflammatory disease of childhood characterized by a combination of systemic features [fever, rash, serositis (e.g., pericarditis, pleuritis)] and arthritis. Current diagnosis of SJIA is based solely on clinical findings [1] and requires arthritis, daily fever for at least 2 weeks, and at least one of the following: evanescent erythematous rash, generalized lymph node enlargement, hepatomegaly and/or splenomegaly, or serositis. This makes early diagnosis of SJIA challenging, as its clinical manifestations are similar to other diseases, including malignancy, infection, Kawasaki disease (KD), and other autoimmune or inflammatory disorders. Long-term disease outcome in SJIA is variable. About 50% of patients experience a single episode that resolves. However, the other half experience either polycyclic or non-remitting disease. Sensitive and specific diagnostic biomarkers for SJIA would allow its differentiation from other febrile illnesses, such as KD or acute infections (febrile illness (FI)), and facilitate prompt initiation of appropriate treatment at disease onset. Early treatment may reduce the risk of long-term complications and subsequent disabilities. In addition, biomarkers that distinguish intercurrent SJIA flare from infection in patients with known SJIA would be clinically useful, as would markers that predict impending disease flare or responder status to particular therapies, or provide an early indication of a treatment response. Finally, biomarkers may provide clues to unanswered questions concerning SJIA pathogenesis.