Motor neurone disease (MND) is a neurodegenerative disorder characterised by the loss of motor neurones, leading to paralysis, with a survival time of two to five years after disease onset. A pathological hallmark of MND is the accumulation of insoluble misfolded protein aggregates in neurones and glia in the spinal cord and/or brain of affected individuals. The accumulation and aggregation of abnormally phosphorylated, ubiquitinated and truncated TransActive Response DNA-Binding Protein of 43 kDa (TDP-43) in the cytoplasm of cells is strongly associated with neurone loss in disease. Sporadic MND (sMND) constitutes ~ 90% of total MND cases, and ~ 97% of sMND cases are associated with protein inclusions enriched in TDP-43. Our lab established a novel flow cytometric assay, flow cytometry of inclusions and trafficking (FloIT), which we have since adapted to provide a 96-well plate high-throughput screening platform designed to identify potential new drugs to treat MND. Using this platform, we have screened numerous small molecules from a number of chemical libraries sourced from Compounds Australia, including ~4,000 FDA approved drugs, 40,000 NatureBank fractions (of ~120,000 natural fractions derived from Australian flora and fauna), and 10,000 Open Scaffold compounds (of ~35,000). Five FDA drugs reduced the numbers of inclusions by 30-40%, with three demonstrating a consistent reduction of TDP-43 inclusions across a range of concentrations as low as 1 μM. Three NatureBank fractions reduced the numbers of TDP-43 inclusions by up to 70%, and the active compound(s) are currently being isolated and identified. These compounds will subsequently be tested in a C. elegans (worm) model, before progression into zebrafish and murine models of MND to determine if compounds can restore locomotion and prevent mortality. This screening platform therefore rapidly identifies potential drug candidates, which can be further tested in a variety of both cell and animal models.