Current therapies for Parkinson’s disease (PD) are limited to managing signs and symptoms; there is no treatment available that prevents or significantly delays progression of the disease. Approximately 10% of PD cases are inherited forms of the disease. Specifically, mutations in the kinase LRRK2 have been shown to cause PD. Previous studies showed that LRRK2 kinase activity is regulated by ArfGAP1 and that decreasing ArfGAP1 expression results in a decrease in toxicity of mutant LRRK2. Therefore, small molecules that inhibit ArfGAP1 may be a potential therapy for PD. To that end, we screened for compounds that inhibit human ArfGAP1. We expressed human ArfGAP1 under the control of a titratable promoter in the yeast Saccharomyces cerevisiae. Expression of human ArfGAP1 in yeast proved toxic to the cell. This toxic phenotype was exploited to perform a high-throughput small-molecule screen for compounds that inhibit ArfGAP1, which would restore viability to the cell. A panel of small molecules was screened, including 5000 pharmacologically active compounds and off-patent FDA-approved drugs, and 100 000 novel small molecules. Six compounds were identified as potential inhibitors of ArfGAP1, all with a similar core structure suggestive of inhibition of the same target. These are being tested for their capacity to inhibit ArfGAP1 directly, and reduce LRRK2 toxicity in vitro and in vivo.