Jérôme Bertherat and colleagues (N. Engl. J. Med. 369, 2105–2114, 2013) identify biallelic inactivation of ARMC5 as a recurrent driver event in corticotropin-independent macronodular adrenal hyperplasia, a rare subtype of Cushing syndrome characterized by multiple, bilateral adrenocortical tumors. Using SNP arrays, the authors analyzed 34 tumor samples from 26 affected individuals and identified a region at 16p11 showing loss of heterozygosity in multiple samples. In parallel, they performed whole-genome sequencing of five tumors and paired normal samples and identified three tumors with somatic alterations in ARMC5, a gene of unknown function mapping to the 16p11 candidate region. Further sequencing of tumor DNA from 33 affected individuals identified 18 samples with ARMC5 alterations, including several nonsense and frameshift mutations. Analysis of constitutive DNA samples from 14 of these individuals identified germline ARMC5 alterations in all cases. More detailed analyses showed that the tumors acquired a second somatic alteration leading to biallelic inactivation of ARMC5, consistent with a two-hit tumor suppressor model. Although further studies are needed to elucidate the pathophysiological mechanisms, ARMC5-mutated tumors exhibit a distinct gene expression signature that may provide insights into deregulated pathways.