The liver is susceptible to the toxic effects of many cytotoxic or immunosuppressive treatments. However, in carriers of hepatitis B virus (HBV) and, less frequently, of hepatitis C virus, liver damage due to reactivation of viral replication can occur after withdrawal of immunosuppressive drugs. These reactivations, which are associated with fulminant forms of hepatitis in up to 25% of cases, are observed both in symptom-free chronic carriers of hepatitis B surface antigen and in patients who have chronic hepatitis B or C and concurrent haematological tumours or solid neoplasms or who have received transplants. HBV-related complications may cause delays or modifications of therapy, and the chance of cure is reduced. In this review, we analyse clinical, biochemical, and serological issues in reactivation of viral replication and examine the role of immune reactions in the pathogenesis and the possible toxicity of immunosuppressive drugs. We emphasise the importance of identifying predictive markers of a clinically relevant reactivation, review difficulties in drug prevention and treatment, indicate studies that are needed to address the key clinical issues, and give practical recommendations to practising physicians and oncologists.