Mice homozygous for albino deletions encompassing the locus alf/hsdr-1 die shortly after birth. Lethality is thought to be the consequence of hypoglycemia, which results from the failure to activate hormone-dependent genes in liver and kidney encoding enzymes important for gluconeogenesis. Within the region in which alf/hsdr-1 has been defined by physical mapping, we identified the gene encoding fumarylacetoacetate hydrolase (FAH), an enzyme of tyrosine metabolism. Lack of FAH activity should lead to accumulation of toxic tyrosine metabolites. In man, genetically determined FAH deficiency is the primary defect in tyrosinemia type I, a fatal liver disease of infants. Northern blot and in situ hybridization analysis of mouse tissues showed that the cell types that normally express FAH correspond to those that exhibit a phenotype in alf/hsdr-1 deletion mice. Moreover, we could mimic aspects of the alf/hsdr-1 deletion phenotype in vitro by treating primary hepatocyte cultures with an intermediate of tyrosine metabolism. These findings strongly suggest that alf/hsdr-1 encodes FAH and that absence of FAH is responsible for neonatal lethality in albino deletion mice. Mechanisms by which this metabolic defect might bring about alterations in gene expression characteristic of the alf/hsdr-1 deletion phenotype are discussed.