Arthritis is the most common cause of disability. Hence, prompt recognition and management of acute-onset polyarthritis are paramount to prevent progressive damage. When rheumatoid arthritis is considered as a prototypical example of polyarthritis, the stakes of early and accurate evaluation are evident. The challenge is in determining when undifferentiated polyarthritis ends and rheumatoid arthritis begins. This chapter reviews the evidence to help clinicians identify and manage patients who present with acute polyarticular inflammation.