The molecular genetics and pathophysiology of Menkes disease and an animal model for this disease are reviewed. The Menkes gene, located on chromosome X13.3, encodes a copper-transporting ATPase, as shown by the sequencing of a cDNA of 4500 bp. Mutations in the Menkes gene in patients with Menkes disease show great variety, including missense, nonsense, deletion and insertion mutations. Mutations in the Menkes gene have also been identified in patients with mild Menkes disease or occipital horn syndrome, showing that these diseases are allelic variants of Menkes disease. Mutations in the mottled gene, the murine homolog of the Menkes gene, have been demonstrated in mottled mutant mice that display biochemical and phenotypic abnormalities similar to those observed in patients with Menkes disease. In affected cells, copper significantly accumulates as metallothionein-bound copper in the cytosol and copper transport to the organelles, as well as copper efflux, is disturbed. As a result, cuproenzymes cannot receive the copper necessary for their normal function. Thus, the objective in treatment of Menkes disease and occipital horn syndrome is to deliver copper to the intracellular compartments where cuproenzymes are synthesized.