Reactivation of hepatitis B virus (HBV) has been often reported as a fatal complication, such as fulminant hepatitis, during or following chemotherapy. It is well-recognized in patients with hepatitis B surface antigen (HBsAg), but notably, it has been reported increasingly in HBsAg negative patients with anti-hepatitis B core antibody (anti-HBc) positivity or anti-hepatitis B surface antibody (anti-HBs) positivity receiving rituximab plus steroid therapy for malignant lymphoma, in whom HBV infection was generally considered to be cured. In Japan, HBsAg positive patients account for ∼1–2% of patients receiving chemotherapy, and HBsAg negative patients with anti-HBc positivity or anti-HBs positivity represent about 20% of the patients. Therefore, establishing a countermeasure for HBV reactivation is an urgent issue, and the Japanese HBV guideline for the prevention of HBV reactivation caused by immunosuppressive therapy or chemotherapy was published in 2009 by the research team at the Japan Ministry of Health, Labour and Welfare. This guideline recommends that the high risk group should be identified by measuring HBsAg levels before the commencement of chemotherapy. If the patients have HBsAg positive serology, the preventive use of an antiviral drug, such as entecavir, is recommended. In HBsAg negative patients, anti-HBc or anti-HBs should be measured before chemotherapy. If either anti-HBc or anti-HBs is positive, HBV DNA should be monitored monthly, and antiviral therapy including entecavir should be begun if HBV DNA becomes positive. However, the frequency of HBV reactivation, the type of chemotherapeutic regimen and the kind of cancer which are associated with easily reactivating HBV have not yet fully been elucidated. Furthermore, the optimal drug for prevention, the duration of prescription of an antiviral drug in patients with HBsAg receiving chemotherapy, and the usefulness of monthly monitoring of HBV DNA in HBsAg negative patients with anti-HBc or anti-HBs positivity have not yet been clarified either. Some well-designed prospective studies are warranted to resolve these issues of HBV reactivation.