Background: Autosomal dominant polycystic kidney disease (ADPKD) is an incurable genetic disease affecting over 500,000 people in the United States and over 12 million people worldwide. If untreated, ADPKD can lead to end-stage kidney failure in about 50% of patients by age 60, which underscores the significant need for therapies that slow down the disease progression while preserving kidney function. The present work describes a small-molecule therapeutic strategy in which the cyst cells are selectively targeted for apoptosis. Methods: A compound denoted 11beta-dichloro, was investigated as a small molecule therapeutic for ADPKD in both a neonate and an adult mouse model of ADPKD. The compound is a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Findings: Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and preserving kidney function in neonatal and adult mouse models of ADPKD. In both models, the cyst cells null for Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of vitamin E antioxidant negated the therapeutic benefit of 11beta-dichloro in vivo, indicating that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features; this derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development. Conclusions: Targeting cystic cells for apoptosis constitutes a promising clinical strategy for ADPKD, with 11beta compounds holding significant potential for development as small molecule therapeutics.