AbstractAs a model disease for the development of suitable gene transfer techniques and their physiological and neurological testing, Lesch‐Nyhan syndrome (LNS) provides important advantages, including the availability of a well‐characterized genetic defect and candidate metabolic targets, as well as a relevant animal model and appropriate gene transfer vectors. On the other hand, the serious gap between the level of characterization of the underlying genetic defects and the resulting neuropathological effects is one of several major impediments to the development of gene therapy. However, the dopamine defect that occurs in LNS may be much more amenable to genetic manipulation than is the deficiency of hypoxanthine guanine phosphoribosyltransferase. A genetic approach to the correction of this intermediate biochemical aberration, which probably is responsible for at least some neurological signs and symptoms of LNS, may be within reach of even the currently imperfect tools of gene therapy. Exploration of this possibility, along with other studies, is likely to lead, slowly but surely, to definition of the conditions under which the genetic and neurophysiological aberrations of LNS will be susceptible to a degree of correction that is not possible by drug therapy alone. © 1995 Wiley‐Lis