Hepatocellular carcinoma is one of the most frequent malignant tumors worldwide: Portal vein tumor thrombosis (PVTT) occurs in about 35%-50% of patients and represents a strong negative prognostic factor, due to the increased risk of tumor spread into the bloodstream, leading to a high recurrence risk. For this reason, it is a contraindication to liver transplantation and in several prognostic scores sorafenib represents its standard of care, due to its antiangiogenetic action, although it can grant only a poor prolongation of life expectancy. Recent scientific evidences lead to consider PVTT as a complex anatomical and clinical condition, including a wide range of patients with different prognosis and new treatment possibilities according to the degree of portal system involvement, tumor biological aggressiveness, complications caused by portal hypertension, patient's clinical features and tolerance to antineoplastic treatments. The median survival has been reported to range between 2.7 and 4 mo in absence of therapy, but it can vary from 5 mo to 5 years, thus depicting an extremely variable scenario. For this reason, it is extremely important to focus on the most adequate strategy to be applied to each group of PVTT patients.