Autosomal dominant polycystic kidney disease (ADpKD) is one of the most common inherited monogenic disorders, characterized by a progressive decline in kidney function due in part to the formation of fluid-filled cysts. While there is one FDA-approved therapy, it is associated with potential adverse effects, and all other clinical interventions are largely supportive. Insights into the cellular pathways underlying ADpKD have revealed striking similarities to cancer. Moreover, several drugs originally developed for cancer have shown to ameliorate cyst formation and disease progression in animal models of ADpKD. these observations prompted us to develop a high-throughput screening platform of cancer drugs in a quest to repurpose them for ADPKD. We screened ~8,000 compounds, including compounds with oncological annotations, as well as FDA-approved drugs, and identified 155 that reduced the viability of Pkd1-null mouse kidney cells with minimal effects on wild-type cells. We found that 109 of these compounds also reduced in vitro cyst growth of Pkd1-null cells cultured in a 3D matrix. Moreover, the result of the cyst assay identified therapeutically relevant compounds, including agents that interfere with tubulin dynamics and reduced cyst growth without affecting cell viability. Because it is known that several ADpKD therapies with promising outcomes in animal models failed to be translated to human disease, our platform also incorporated the evaluation of compounds in a panel of primary ADPKD and normal human kidney (NHK) epithelial cells. Although we observed differences in compound response amongst ADPKD and NHK cell preparation, we identified 18 compounds that preferentially affected the viability of most ADPKD cells with minimal effects on NHK cells. Our study identifies attractive candidates for future efficacy studies in advanced pre-clinical models of ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) has a prevalence of 1 in 500-1,000 individuals and is the most common inherited kidney disease, accounting for 6-9% of patients on renal replacement therapy. ADPKD is caused mainly by mutations in PKD1 and to a lesser extent in PKD2, GANAB and DNAJB11 genes. The disease is characterized by a progressive decline in kidney function due to the formation of fluid-filled cysts as well as activation of inflammatory and proliferative pathways, typically leading to end-stage renal disease by the fifth or sixth decade of life 1. Although cyst formation in the kidneys is the hallmark of ADPKD, other epithelial organs including the liver and pancreas are also commonly affected 2,3. With the 2018 FDA approval of Tolvaptan, a vasopressin V 2-receptor antagonist, there is now one therapy available to slow disease progression; however, the drug was only approved for patients at risk of rapid disease progression due to its potential side effects. Nevertheless, most interventions focus on alleviating disease-related symptoms.