Cheung and colleagues report aberrations in the PI3K pathway occur in a majority of endometrioid endometrial cancers, with coordinate mutations of multiple pathway members being more common than predicted by chance. Multiple gain-of-function PIK3R1 and PIK3R2 mutations result in the stabilization of PTEN protein with likely contribution from the ubiquitin-proteasome degradative pathway, as depicted by the cover. For details, please see the article by Cheung and colleagues on page 158.