Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a high mortality rate. While chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent the leading risk factors worldwide, the spreading of metabolic disorders, such as diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) justifies the increasing attention on their oncogenic mechanisms. This review discusses about the main pathogenic mechanisms implicated in occurrence of HCC in presence of viral and metabolic diseases. Additionally, it points to the importance of clinical surveillance for those patients considered at risk of HCC and highlights the strategical role of serum markers, such as alfa-fetoprotein (αFP) and Protein Induced by Vitamin K Absence or Antagonist II (PIVKA-II), which, in association to a strictly instrumental follow-up, contribute to the early detection of hepatic nodules with a better prognosis for affected patients. Journal of Cancer Therapy thanks to new effective antiviral therapies, it represents one of the predominant causes of malignancy-related death worldwide [1]. The leading incidence of HCC in metabolic disorders motivates the clinical approach to the emergent pre-cancerogenic role of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and justifies the leading scientific interest for the metabolic factors that contribute to their pathogenesis. Moreover, the spreading of metabolic disorders, in addition to known viral risk factors, has required a strictly clinical observation in those patients considered at risk in order to achieve an early diagnosis of HCC.D. Sciancalepore et al.