Hepatitis E virus (HEV) is yearly responsible for approximately 20 million infections worldwide. Although most infections occur in developing countries, HEV appears to be an emerging problem in several industrialized countries, where it is mostly associated with either traveling to an HEV endemic area or contact with pigs, which represent a major reservoir of HEV. The major risk groups for HEV infection and its ensuing complications are elderly men, pregnant women, young children, immunocompromised patients, patients with preexisting liver disease, and workers that come into close contact with HEV-infected animals. Whereas HEV mainly causes acute self-limiting infections, chronic infections may occur among immunocompromised patients (e.g., transplant recipients and human immunodeficiency virus [HIV]-infected patients). Accordingly, HEV-HIV coinfection leads to accelerated liver cirrhosis and increased mortality rates compared to HEV infection alone, which is, except during pregnancy, usually associated with only low mortality. In the Western world, the most common genotype (gt) causing HEV infection is gt 3. Ribavirin (RBV) and interferon have been used successfully for treatment of HEV, but this treatment is contraindicated in certain patient groups. Therefore, novel antiviral compounds are highly needed, especially given that viral isolates with RBV resistance have been recently identified. Moreover, eradication of HEV is hampered by long-term environmental persistence of the virus, which represents a continuous source of the virus. In 2011, the first prophylactic HEV vaccine, Hecolin, was approved in China, but it is not yet globally available. In this review, we will discuss the molecular virology of HEV, mode of transmission in industrialized countries, and potential implications for different specific patient populations.