Hepatitis B virus reactivation (HBVr) is an important complication of immunosuppressive drug therapy (ISDT). It can occur with active or resolved hepatitis B virus (HBV) infection with a clinical spectrum that ranges from mild elevations in liver tests to fulminant hepatic failure. The risk of it occurring is determined by the interplay between HBV serological status, level of viremia, and the immunosuppressive potency of the drug(s) used. Reactivation is most common during treatment of hematologic malignancies but also occurs with chemotherapy for breast cancer and numerous other solid organ malignancies, organ transplant, and immune suppression for nonmalignant conditions. The expansion of new biologic treatments for malignant and nonmalignant disorders has enlarged the population at risk. Increased awareness of HBVr among healthcare providers who prescribe ISDT, adoption of routine HBV screening, and linking the results of screening to antiviral prophylaxis are needed to reduce the incidence of this potentially fatal but preventable disorder.