Patients suffering from rare human diseases often go through a painful journey for finding a definite molecular diagnosis prerequisite of appropriate cures. With a novel variant isolated from a single patient, determination of its pathogenicity to end such “diagnostic odyssey” requires multi-step processes involving experts in diverse areas of interest, including clinicians, bioinformaticians and research scientists. Recent efforts in building large-scale genomic databases and in silico prediction platforms have facilitated identification of potentially pathogenic variants causative of rare human diseases of a Mendelian basis. However, the functional significance of individual variants remains elusive in many cases, thus requiring incorporation of versatile and rapid model organism (MO)-based platforms for functional analyses. In this review, the current scope of rare disease research is briefly discussed. In addition, an overview of invertebrate MOs for their key features relevant to rare neurological diseases is provided, with the characteristics of two representative invertebrate MOs, Drosophila melanogaster and Caenorhabditis elegans, as well as the challenges against them. Finally, recently developed research networks integrating these MOs in collaborative research are portraited with an array of bioinformatical analyses embedded. A comprehensive survey of MO-based research activities provided in this review will help us to design a wellstructured analysis of candidate genes or potentially pathogenic variants for their roles in rare neurological diseases in future.