Ceramide is the central lipid of sphingolipids and is metabolized by various metabolic enzymes. Sphingolipids play important roles as a constituent of biological membranes and exert multiple physiological functions. Thus, understanding the physiological functions of ceramide metabolism enzymes will lead to elucidation of various diseases and drug discovery. There are three therapeutic agents targeting ceramide-related metabolism enzyme or receptor. Recently, we and other groups have found that ceramide metabolism enzymes may be therapeutic targets for Niemann-Pick disease type C (NPC). NPC is a lipid storage disorder caused by mutations in NPC1 or NPC2 genes. While cholesterol is well known to be accumulated in NPC, multiple species of sphingolipids accumulate as well. We found that ceramide-1-phosphate (C1P), a phosphorylated ceramide produced by ceramide kinase (CerK), levels were increased in NPC1^−/− cells, NPC1 mutant cells, NPC1^−/− mouse brain, and the plasma from the patients with NPC. CerK inhibition decreased free cholesterol accumulation in NPC1^−/− cells, NPC1 mutant cells, and patient-derived induced pluripotent stem cell neurons. C1P accumulation in NPC1^−/− cells negatively regulated the transport of LDL-derived free cholesterol to the endoplasmic reticulum. Genetic deletion of CerK in NPC1^−/− mice attenuated cholesterol accumulation in the cerebellum, improved Purkinje cell survival, and prolonged lifespan. These results suggest that CerK is a novel therapeutic target for NPC.