Genetic and developmental factors were investigated in 101 cases of canine narcoleps-cataplexy syndrome. An experimental breeding program documented a probable autosomal recessive mode of inheritance in two dog breeds, Doberman pinschers and Labrador retrievers, and in crosses between those breeds. Age of onset of cataplexy and severity of symptoms were remarkably similar in 73 subjects with the genetically transmitted form of narcolepsy. Efforts to demonstrate genetic factors by breeding affected poodles and beagles were unsuccessful. Furthermore, a positive family history could not be documented in these animals or in narcoleptic dogs of 13 other breeds. Both age of onset and severity of symptoms were highly variable within this population. We suggest there may be multiple etiologies in canine narcolepsy syndrome: (i) inheritance via a single autosomal recessive gene, which appears to be identical in at least two unrelated dog breeds; (ii) nongenetic mechanisms which may include developmental or traumatic accidents. Preliminary findings of parallel neurochemical studies in narcoleptic dogs indicate distinct abnormalities in central neurotransmitter concentration and turnover. We theorize that these neurochemical abnormalities may result from inherited disorders of synthesis and/or metabolism which are present from birth or from nongenetic neurochemical abnormalities appearing later in life. The observation that symptom characteristics are identical in all affected dogs suggests that a common neurochemical disorder may underlie both genetic and nongenetic variations of the disease.