Endometriosis is a common gynecological disease characterized by the ectopic growth of endometrium-like tissue. Despite the widespread prevalence of endometriosis, its pathogenesis remains poorly understood. A recent study by Noë et al provides evidence that the epithelium and stroma within the same endometriotic lesions follow distinct and independent developmental trajectories. They used droplet digital polymerase chain reaction analysis of laser-captured epithelium-enriched and stroma-enriched endometriosis tissue, and found that all 19 somatic passenger mutations analyzed were enriched exclusively in the epithelial compartment. These findings are consistent with the clonal expansion of epithelial cells, whereas stromal cells may be continuously regenerated or recruited over the course of disease. Further findings of differing allelic frequencies among passenger mutations within the epithelium of the same endometriotic lesions are suggestive of subclonality or the existence of multiple clones in some cases. Overall, the authors' observations of clonally dominant somatic passenger mutations in the epithelium and not the stroma of endometriosis add to the recent description of cancer-associated mutations in such lesions, and provide clues to the pathogenesis of endometriosis. Further studies to determine where and when these mutations occur and whether they can be used to develop the first biologically informed classification system for endometriosis are warranted. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.