Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Limitations of the current dietary treatment for PKU have led to the development of potential treatments based on somatic gene transfer. Three different vector systems have been examined. Vectors derived from a recombinant retrovirus or a DNA/protein complex can efficiently transduce the PAH cDNA into PAH-deficient hepatocytes in vitro, but the application of these vector systems is presently limited by their low transduction efficiency in vivo. In contrast, a vector derived from a recombinant adenovirus can restore 10%-80% of normal hepatic PAH activity into PAH-deficient mice, which completely normalizes serum phenylalanine levels. This treatment is transient and cannot be effectively re-administered due to the presence of neutralizing antibodies directed against the recombinant adenoviral vector. However, these findings suggest that PKU can be completely corrected by somatic gene therapy, and provide some direction for the future development of adenoviral vectors.