Alterations of hepatic metabolism are critical to the development of liver disease. The peroxisome proliferator-activated receptor-γ coactivators (PGC1s) are able to orchestrate, on a transcriptional level, different aspects of liver metabolism, such as mitochondrial oxidative phosphorylation, gluconeogenesis and fatty acid synthesis. As modifications affecting both mitochondrial and lipid metabolism contribute to the initiation and/or progression of liver steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), a link between disrupted PGC1 pathways and onset of these pathological conditions has been postulated. However, despite the large quantity of studies, the scenario is still not completely understood, and some issues remain controversial. Here, we discuss the roles of PGC1s in healthy liver and explore their contribution to the pathogenesis and future therapy of NASH and HCC.