Hepatitis E virus (HEV) infects approximately 20 million individuals each year all around the world, both in developing and industrialized countries. It leads to 40,000– 70,000 deaths annually, especially in immunocompromised patients and pregnant women. Despite its recognized major public health issue status and zoonotic potential, no specific treatment is available. Indeed, HEV life cycle characterization is hampered by the lack of efficient infectious cell culture systems or in vivo models. A better knowledge of HEV virology is therefore needed. By providing descriptions of the three-dimensional structures of viral proteins at atomic level, structural biology can be a powerful tool to understand viral replication and help develop specific antivirals. In this comment, we describe how both experimental and advanced computational structural biology help to decipher HEV virology and make a case for heeding its lessons.