Reactive arthritis (ReA) has traditionally been described as a nonseptic arthritis occurring in the joint following an extra-articular bacterial infection. This concept became clinically associated with antecedent infections of either the gastrointestinal or genitourinary tract. Yet this operational definition of ReA has led to diagnostic uncertainty in different clinical settings. There are several scenarios in which the ReA has been complex. One is in the SAPHO syndrome, which shares many features with ReA. Another is the development of arthritis after infection with atypical organisms such as Clostridium difficile and Giardia lamblia. Treatment of ReA remains an area of ongoing investigation. There has been a randomized controlled trial of combination antibiotics in Chlamydia-induced ReA, which reported a positive result. There are several uncontrolled reports of anti-TNF agents being used successfully in refractory ReA. These studies in treatment modalities require validation on larger samples but do provide some encouraging preliminary findings from which to develop new therapeutic approaches.