Liver gene therapy is being developed as an alternative to orthotopic liver transplantation, which is the only effective therapy for many liver diseases. The liver has unique features that make it attractive for in vivo and ex vivo gene transfer. In vivo approach is far less invasive than ex vivo approach, although in most cases, host immune response directed against the transgene product and/or vector particles severely impairs the efficiency of gene transfer, and precludes long-term transgene expression after in vivo gene delivery. Ex vivo approach allows for an elective targeting of the hepatocytes, avoiding that the transgene be expressed in professional antigen-presenting, but is faced with the low in vitro proliferative ability of hepatocytes, and to the low in vivo liver repopulating ability of transplanted cells. In some specific situations where immune response was controlled or transplanted cells had a strong growth advantage over host hepatocytes, gene transfer resulted in long-term and complete correction of a liver genetic defect. In this review, we will outline the liver diseases that may benefit from gene therapy, the vector technology under investigation, the advances and the problems to be overcome.