Very recently, an unusual clinical presentation with an altered natural history associated with hepatitis E virus (HEV) infection has emerged in high-income industrialized nations. Although HEV infection does not develop into chronicity in general, viremia can persist for long periods of time in immunocompromised solid organ, bone marrow and stem cell transplant patients. Conceivably, the atypical clinical and virological outcomes in these cases could be related to immunosuppressive chemotherapy, resulting in suboptimal HEV-specific immune responses. In the absence of travel to endemic regions, foodborne autochthonous HEV infection due to viral genotypes 3 and 4 has been implicated in the chronic cases. Presently, pegIFN-α-2a and ribavirin, the commonly used drugs to treat chronic viral hepatitis, are proving very promising in hepatitis E patients. Nevertheless, the most-awaited HEV vaccine could be protective in naïve travelers or high-risk group populations. The mechanisms of establishing chronic HEV infection and the disease severity have hitherto not been clearly understood. Therefore, a comprehensive clinical, virological and molecular study is needed to understand and control the disease.