Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.