The tumor suppressor PTEN is a protein/phosphoinositide phosphatase regulating the PI3K/Akt signaling pathway and is mutated or deleted in a variety of human cancers, including hepatocellular carcinoma (HCC). Accumulating evidence indicates that alterations of PTEN expression and activity in hepatocytes are common and recurrent molecular events associated with liver disorders of various etiologies including obesity, the metabolic syndrome, hepatitis B virus/hepatitis C virus infection and abusive alcohol consumption. Genetic and molecular studies, particularly in the context of non-alcoholic fatty liver disease (NAFLD), support a critical role for PTEN in hepatic insulin sensitivity and the development of steatosis, steatohepatitis and fibrosis. PTEN mutations/deletion or low PTEN expression are also associated with diverse liver malignancies, suggesting a critical role for PTEN in hepatic cancers. This review provides an overview of the current knowledge on pathological dysregulations of PTEN expression/activity in the liver with obesity and the metabolic syndrome, and the role of this enzyme in the development of non-alcoholic fatty liver disease and hepatocellular carcinoma.