Proton pump inhibitors (PPIs) have been among the most widely prescribed medications in the United States for decades. This is largely due to 2 very common uses of PPIs: treatment of dyspepsia and prevention of gastrointestinal bleeding among patients prescribed antiplatelet therapy, coupled with the belief that PPIs have few adverse effects. However, mounting evidence demonstrates that PPIs are associated with a number of adverse effects and are overprescribed. This issue was highlighted in JAMA Internal Medicine’s launch of the Less Is More series in 2010.1,2 Since then, additional evidence of adverse effects of PPIs has accumulated. In this issue of JAMA Internal Medicine, Lazarus et al3 add chronic kidney disease to the list of possible harms of PPIs.