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Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species., Author Summary Spinal Muscular Atrophy (SMA) is a common, untreatable, and often fatal neuromuscular disease predominately caused by reduced Survival Motor Neuron (SMN) protein function. Here, we use invertebrate models to identify and validate conserved genes that play a critical role in SMN loss of function neuromuscular defects. Decreased SMN function causes growth defects in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster—as well as behavioral or synaptic connectivity defects between neurons and muscles, respectively. We found that a genetic modifier of SMA in patients, plastin, also affects SMN function in these invertebrate models. We undertook a genome-wide RNAi screen to identify genes whose perturbation alters the growth defects of C. elegans lacking SMN. These genes were validated in neuromuscular assays in nematode and fly models of SMA. Additionally, we used the C. elegans model to test SMN modifier genes previously identified in the Drosophila SMA model. Combined, these cross-species approaches identified fifteen genes that are important in both species when SMN function is decreased. Related mammalian proteins and the pathways in which they act (including endocytosis and RNA transport/translational control) are likely important players in SMA.