Despite the major advances towards better prevention and treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, these two chronic infections still account for ∼500 million infected people and 1 million deaths per year worldwide. Rheumatologists are frequently encountering patients with rheumatic disease who have co-existing HBV or HCV infection in daily clinical practice. Moreover, over the past decade, a number of studies have shown an increased risk of HBV reactivation and liver-related complications in HBV-infected patients treated with biologic agents (especially anti-TNF therapies). In this Review, the basic viral characteristics of HBV and HCV, as well as the natural course of chronic HBV and HCV infection, are outlined. Furthermore, a rational clinical approach for diagnosis and treatment of these comorbid conditions in the context of rheumatic disease is presented.