Inherited metabolic diseases (IMD) are attractive targets for gene therapy because of their severity, high overall prevalence, lack of effective treatments, and possibility of early diagnosis by newborn screening. The liver is a central organ involved in metabolism and thus, it is an important target for gene therapy of IMD. Adeno-associated virus (AAV) vectors are emerging as the preferred vectors for in vivo gene delivery. Gene replacement strategies are aimed either at correcting liver disease or providing a source for production and secretion of the deficient enzyme for cross-correction of other tissues. In this talk, I will present updates on ongoing AAV-mediated, liver-directed gene therapy clinical trials for two diseases, namely Mucopolysaccharidosis type VI (MPS VI), a multisystem lysosomal storage disorder due to deficiency of arylsulfatase B (ARSB), and Crigler-Najjar syndrome due to deficiency of uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) enzyme resulting in severe unconjugated hyperbilirubinemia. MPS VI patients are currently treated with Enzyme replacement therapy (ERT). However, ERT requires life-long and costly intravenous infusions that have limited efficacy on some diseased tissues. Patients with Crigler-Najjar syndrome are currently treated with prolonged, daily phototherapy that partially controls jaundice and the only definitive therapy is liver transplantation. In nine participants with MPS VI treated with gene therapy, we did not observe a dose-limiting side effect and the high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. In patients with Crigler-Najjar syndrome, AAV vector was also found to be safe and effective at restoring liver UGT1A1 function to levels allowing for phototherapy withdrawal. In conclusion, by providing long-term hepatic expression of the therapeutic gene, AAV-mediated gene therapy is an attractive approach for therapy of IMD.