We have generated an acid sphingomyelinase (aSMase)-deficient mouse line by gene targeting. This novel strain of mutant mouse mimics the lethal, neurovisceral form of the human sphingomyelin storage disease, known as Niemann-Pick disease. Homozygous mice accumulate sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, and in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerates completely, leading to severe impairment of neuromotor coordination. The Niemann-Pick mouse might facilitate studies on the function of aSMase in the generation of ceramide as proposed second messenger in the intracellular signaling pathways and across the plasma membrane. Furthermore, it provides a suitable model for the development of strategies for somatic gene therapy.