Introduction of biologic agents to treat patients with rheumatic diseases and cancer has improved clinical outcomes. However, this advance increases the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen carrier and even in resolved HBV infection, which can lead to liver failure and even death. In particular, the risk of HBV reactivation is heightened by the use of B-cell depleting agents such as rituximab, high dose corticosteroid, and anti-tumor necrosis factor-α. Therefore, identification of individuals at risk, and understanding the mechanism of HBV reactivation are essential to preventing HBV reactivation before initiating immunosuppressive therapy. Here, we review the mechanism, incidence, and prevention of HBV reactivation in the setting of immunosuppression.