The exponential accumulation of DNA sequencing data has opened new avenues for discovering the causative roles of single-nucleotide polymorphisms (SNPs) in neurological disease. The opportunities emerging from this are staggering, yet only as good as our abilities to glean insights from this surplus of information. While computational biology continues to improve with respect to predictions and molecular modeling, the differences between in silico and in vivo analysis remain substantial. Invertebrate in vivo model systems represent technically advanced, experimentally mature, high-throughput, efficient, and cost-effective resources for investigating disease. With a decades-long track record of enabling investigators to discern function from DNA, fly (Drosophila) and worm (C. elegans) models have never been better poised to serve as living engines of discovery. Both of these animals have already proven useful in the classification of genetic variants as either pathogenic or benign across a range of neurodevelopmental and neurodegenerative disorders—including autism spectrum disorders, ciliopathies, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s disease. Pathogenic SNPs typically display distinctive phenotypes in functional assays when compared to null alleles, and they frequently lead to protein products with gain-of-function or partial loss-of-function properties that contribute to neurological disease pathogenesis. The utility of invertebrates is logically limited by overt differences in anatomical and physiological characteristics, and also evolutionary distance in genome structure. Nevertheless, functional annotation of disease-SNPs using invertebrate models can expedite the process of assigning cellular and organismal consequences to mutations, ascertain insights into mechanisms of action, and accelerate therapeutic target discovery and drug development for neurological conditions.