Liver injury in the HIV-positive population has been classically associated with hepatitis B or C viruses (HBV and HCV). While HBV or HCV co-infections have represented “Pillars of Hercules” for hepatic disease (not further beyond), it is now time to move forward and shed light on liver disease in HIV-infected patients without HBV or HCV co-infections. Indeed, over the last years, liver disease in HIV-mono-infected patients has emerged and fated to become one of the main non AIDS-related complications. Although several cases have specific etiologies (e.g., alcohol abuse), other cases are most challenging for the clinicians because the actual causes are only hypothesized, such as it is difficult to treat them appropriately. This new clinical entity has been named “cryptogenic” liver disease; it is polymorphic (e.g., hepatic steatosis, nodular regenerative hyperplasia or noncirrhotic portal hypertension) and multifactorial in nature, but HIV per se may play a key role. In this paper, we present a critical review of the relevant literature data, focusing on practical implications (including diagnostic tools and differential diagnosis), and delineate priorities for future research on this important topic.