Many facets of the pathogenesis of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease manifested with severe motor neuron dysfunction, are beginning to be uncovered. One of the major implicated proteins in the ALS pathogenesis is the TAR DNA-binding protein 43 (TDP-43) and its dyshomeostasis has been extensively modeled in the mammalian systems to examine the ALS-associated TDP-43 proteinopathy mechanisms. Here, we discuss the insights of the TDP-43 proteinopathy mechanisms that have been unearthed from simplistic, yet highly informative, four nonmammalian model systems: the yeast Saccharomyces cerevisiae, the fly Drosophila, the nematode worm Caenorhabditis elegans, and a vertebrate zebrafish. These models have elucidated the role of several key metabolic and genetic pathways in the TDP-43 proteinopathies and identified therapeutic targets, which have been discussed here. © 2022 Elsevier Inc. All rights reserved.