Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide, accounting for 20 million infections per year and 70,000 deaths. In developed regions, sporadic locally acquired infections are most commonly caused by HEV3, and in this setting Hepatitis E is mainly asymptomatic. However, certain group of patients HEV infection may present as a fulminant disease or progressive fibrosis. Chronic HEV infection can occur in immunocompromised individuals, including transplant recipients. A high proportion of solid-organ transplant recipients exposed to HEV are at risk of developing a chronic infection, frequently associated to extrahepatic manifestations. However, clinical phenotype of sporadic cases of HEV infection is still poorly characterized. A recent work, focused on the retrospective study of HEV as a causative agent of viral hepatitis in adults form Mexico, pose novel challenges to understanding the HEV threat to human health. Main findings are brought into discussion herein, in light of the current knowledge concerning viral pathogenesis and host–pathogen interaction. The role of HEV infection in the development of chronic liver disease is also discussed. Hepatitis E is a cause of mortality and morbidity which negatively impacts the prognosis of patients with chronic liver disease. Recognition of HEV infection must be improved, by increasing awareness and knowledge of the clinical phenotype of the disease.