Niemann-Pick type C (NPC) disease is a panethnic lysosomal lipidosis, which results in severe cerebellar impairment and death, and is proposed to be a consequence of defective metabolite transport. Numerous models of this disorder have defined the phenotypic impact of misfunction of the NPC proteins, however, their mechanism of action and definition of substrate(s) remain vague and disputed. The proteins may be lipid chaperones, nonspecific transporters, orphan transporters or membrane-sensing regulators ('rheostats') of other transport reactions. These issues pertain to the nature or even existence of a toxic metabolite as causative to this disorder and thus ultimately to treatment of the disease. This review will present the issues that underpin NPC disease and current or future avenues of treatment.