Ongoing advances in liver disease management and basic research in recent years have changed our knowledge of the natural history of hepatocellular carcinoma (HCC). Indeed, the natural history of this tumor is fairly long and covers a preclinical and a clinical phase. Some of the biological steps involved in cell transformation and different carcinogenic pathways have been identified, disclosing potential novel markers for HCC. Following the progress in surveillance and early diagnosis, much more is now known about precancerous lesions and the process leading to overt HCC, including growth patterns, dedifferentiation and neoangiogenenesis. In particular, research has focused on clinical and biological factors predicting tumor aggressiveness and patients’ prognosis. Lastly, clinical studies have described tumor presentation, evolution and causes of patients’ death and how the new knowledge has influenced clinical management and patients’ survival in recent years. By addressing 10 key questions, this review will summarize well-established and novel features of the natural history of HCC.