Chronic hepatitis B virus (HBV) infection is endemic in the Asian-Pacific region, and reactivation of HBV post-cancer chemotherapy has become an emerging clinical challenge. Patients with detectable serum HBV DNA before chemotherapy and those receiving intensive chemotherapy are particularly at a risk of HBV reactivation. Most patients with HBV reactivation are positive for hepatitis B surface antigen (HBsAg) and are, therefore, easily identified by recommended serological screening before chemotherapy. However, a small, but significant proportion of subjects who have apparently recovered from HBV infection as reflected by HBsAg negativity and hepatitis B core antibody positivity in HBV endemic areas may also experience reactivation when host immunity is severely compromised by cancer chemotherapy. Serum alanine aminotransferase, HBsAg, and/or HBV DNA should be monitored closely in these subjects and antiviral therapy should be administered immediately when any evidence of HBV reactivation is detected during chemotherapy. The prophylactic use of nucleos(t)ide analogs before chemotherapy and its continuation until reconstitution of host immunity remain the mainstay of effective prevention of hepatitis B reactivation in this special clinical entity.