Hepatitis B virus (HBV) reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents. In particular, the risk of HBV reactivation is heightened by the use monoclonal antibodies, such as rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. Emerging data indicate that HBV reactivation could also develop following the use of other biologic agents, such as tumor necrosis factor (TNF)-alpha inhibitors. When HBV reactivation is diagnosed, it is mandatory to suspend biologic treatment and start antiviral agents immediately. However, pre-emptive antiviral therapy prior to monoclonal antibody administration is crucial in preventing HBV reactivation and its clinical consequences. Several lines of evidence have shown that risk of HBV reactivation is greatly reduced by the identification of high-risk patients and the use of prophylactic antiviral therapy. In this article, we discuss current trends in the management of HBV reactivation in immunosuppressed patients receiving biologic therapy, such as rituximab, alemtuzumab and TNF-alpha antagonists. (C) 2011 Baishideng. All rights reserved.