: The liver is particularly amenable to gene therapy as it is the site of many metabolic diseases and malignancies. Thus, liver‐directed gene therapy is being actively pursued and developed as a method of treatment for various liver diseases. Strategies of liver‐directed gene therapy include drug delivery to the liver, compensation of the defective gene(s), anti‐tumor activity, anti‐viral therapy, and immunomodulation. The strategy chosen for liver‐directed gene therapy depends on the genetic basis of the disease. Many aspects are key factors to the success of the chosen strategy: intervention of genes, efficient gene delivery system, stable transgene expression, transgene regulation, target cell transfection, and timing of transgene expression. Several tactics can be used to overcome problems in the above, and these include the use of a gene switch to exogenously regulate transgene expression, targeting at the transcriptional level, circumvention of the immune response (as in the use of adenovirus vector to achieve long‐term correction of genetic diseases), and genetically engineered antibodies in gene transfer. At the present rate of research activity and development, gene therapies may soon be more efficient than current standard treatments for some liver diseases.