Introduction: Mucopolysaccharidosis type III (MPS III) is a rare disorder characterized by progressive neurocognitive impairment. No disease-modifying treatment is yet available but many are currently under study. The aim of this review is to report on the results of the first clinical trials in MPS III and to discuss specific challenges and recommendations in trial design. Areas covered: Gene therapy, enzyme replacement therapy and substrate reduction therapy for MPS III. Expert opinion: Although some trials have been stopped because of lack of effect, several other phase I/II studies have reported data suggesting a positive effect of treatment. A number of treatment options will enter phase III trials in the very near future. However, several challenges have emerged. The rarity of the disease limits the number of potential patients per trial and competition for eligible patients is imminent. Furthermore, high quality natural history data will be essential to serve in trials as a comparator arm. This can only be achieved by rapid publication, full transparency and sharing of all available natural history data. Also, the broad phenotypic spectrum may complicate assessment of treatment efficacy, and phenotypic prediction is therefore essential. Finally, as early initiation of treatment is needed to demonstrate maximal, or even sufficient, treatment effect, newborn screening for MPS III will, in the end, be needed.