Occult hepatitis B virus (HBV) infection is a world-wide entity, following the geographical distribution of detectable hepatitis B. This entity is defined as the persistence of viral genomes in the liver tissue and in some instances also in the serum, associated to negative HBV surface antigen serology. The molecular basis of the occult infection is related to the life cycle of HBV, which produces a covalently closed circular DNA that persists in the cell nuclei as an episome, and serves as a template for gene transcription. The mechanism responsible for the HBsAg negative status in occult HBV carriers is a strong suppression of viral replication, probably due to the host's immune response, co-infection with other infectious agents and epigenetic factors. There is emerging evidence of the potential clinical relevance of occult HBV infection, since this could be involved in occult HBV transmission through orthotopic liver transplant and blood transfusion, reactivation of HBV infection during immunosuppression, impairing chronic liver disease outcome and acting as a risk factor for hepatocellular carcinoma. Therefore it is important to bear in mind this entity in cryptogenetic liver diseases, hepatitis C virus/HIV infected patients and immunosupressed individuals. It is also necessary to increase our knowledge in this fascinating field to define better strategies to diagnose and treat this infection.