Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations. Reactivation is frequently induced by medical treatments such as cancer chemotherapy, antirejection drugs used in organ transplantation, and corticosteroids. The immunologic flares that often result from sudden withdrawal of these medications can be life-threatening unless recognized and treated promptly with antivirals, and there is increasing experience that preemptive antiviral treatment can diminish their occurrence and improve the outcome. The experience with lamivudine and other nucleoside analogues has increased our understanding of the molecular events behind hepatitis flares that occur when chronic hepatitis B is treated with drugs that potently inhibit HBV DNA polymerase. However, not all flares are explainable by events related to HBV infection alone. Depending on the population studied, as many as 20%-30% of flares may be caused by infection with other hepatotropic viruses, and this situation may inhibit HBV replication. Proper understanding of the etiology and effective treatment of acute flares in chronic hepatitis B requires an appreciation of high-risk clinical situations, assessment of HBV replication status, and testing for other viruses when appropriate.