This case series is to create awareness among clinicians on the importance of Hepatitis B screening prior to administration of chemotherapeutic agents and immunosuppressant in preventing Hepatitis B reactivation (HBVr). We also highlight the importance of identifying patients who are at risk of HBVr and when to initiate antiviral prophylaxis based on the current evidence-based guidelines. The case series consists of four patients seen in Hospital Selayang, Malaysia who developed fulminant liver failure secondary to chemotherapeutic agents or immunosuppressant induced HBVr. HBVr is likely to be of increasing clinical significance as potent immunosuppressive regimens are used more widely across all medical specialties. Clinicians should be made aware of the potential risk of patients developing fulminant liver failure following HBVr and its association with high morbidity and mortality. In the era of inexpensive Hepatitis B blood screening tests and safe potent antivirals, there is now a paradigm shift to make the test compulsory to screen all patient prior to initiation of chemotherapeutic agents or immunosuppressive therapy. Antiviral prophylaxis may be offered to more patients who are at risk of HBVr and the duration of both prophylaxis and subsequent monitoring may be extended until 6 to 18 months following completion of treatment.