ImportanceRoux-en-Y gastric bypass (RYGB) remains one of the most commonly performed operations for morbid obesity and is associated with significant long-term weight loss and comorbidity remission. However, health care utilization rates following RYGB are high and abdominal pain is reported as the most common presenting symptom for those seeking care.ObservationsGiven the limitations of physical examination in patients with obesity, correct diagnosis of abdominal pain following RYGB depends on a careful history and appropriate use of radiologic, laboratory and endoscopic studies, as well as a clear understanding of post-RYGB anatomy. The most common etiologies of abdominal pain after RYGB are internal hernia, marginal ulcer, biliary disease (eg, cholelithiasis and choledocholithiasis), and jejunojejunal anastomotic issues. Early identification of the etiology of the pain is essential, as some causes, such as internal hernia or perforated gastrojejunal ulcer, may require urgent or emergent intervention to avoid significant morbidity. While laboratory findings and imaging may prove useful, they remain imperfect, and clinical judgment should always be used to determine if surgical exploration is warranted.Conclusions and RelevanceThe etiologies of abdominal pain after RYGB range from the relatively benign to potentially life-threatening. This Review highlights the importance of understanding key anatomical and technical aspects of RYGB to guide appropriate workup, diagnosis, and treatment.