Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. It is an underdiagnosed disease because of the use of low-sensitivity serological assays; however, diagnostics tools, including nucleic-acid tests, have improved. HEV infection is usually an acute self-limiting disease, but causes chronic infection with rapidly progressive cirrhosis in adult and pediatric organ-transplant-patients. HEV infection evolves to chronic hepatitis in nearly 60% of HEV-infection solid-organ-transplant patients. HEV can also cause extra-hepatic manifestations, such as neurological symptoms and kidney injury. Reducing immunosuppression in transplant patients can lead to HEV clearance in one-third of patients with chronic hepatitis. The use of anti-viral therapies, such as pegylated-interferon and ribavirin, has been found to efficaciously treat HEV infection.