ATMdepletion is associated with the multisystemic neurodegenerative syndrome ataxia–telangiectasia (A–T). The exact linkage between neurodegeneration andATMdeficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes inATMdeficiency to highlight potential targets for the treatment of neurodegeneration in A–T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage onATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genesSAV1andNF2, as well as chemical inhibition of this pathway, specifically promoted the growth ofATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A–T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulatorBAG6, as synthetic viable withATM-deficiency. These genes may help to develop drugs for the treatment of A–T patients as well as to define biomarkers for resistance toATMinhibition-based chemotherapies and to gain new insights into theATMgenetic network.