Abstract Juvenile Neuronal Ceroid Lipofuscinosis is a lysosomal storage disease characterized pathologically by intracellular accumulation of autofluorescent storage material and neurodegeneration. Caused by mutations in the CLN3 gene on chromosome 16p12, the precise functions of the encoded protein remain unclear. Yet, recent preclinical discovery has established new therapeutic targets in development, including immunosuppressants, anti-inflammatories, and gene replacement therapies. Development of robust clinical trial endpoints appropriate for this poly-symptomatic disease, clinical trial design optimized for small samples, and adequate and efficient participant recruitment are challenges that lay ahead.