The diagnosis of cholecystitis and cholelithiasis is often straightforward, particularly when transabdominal ultrasound (TUS) reveals gallstones or other abnormalities of the gallbladder. There remain many patients, however, with typical biliary pain and normal findings on TUS. This latter group of patients, in which women constitute a large majority, often undergo considerable suffering. Their medical care can also be quite costly. Cholecystokinin cholescintigraphy and stimulated biliary drainage (SBD) have been proposed for difficult-to-diagnose gallbladder disease, but they both have limitations. Cholecystokinin cholescintigraphy may not predict postoperative outcomes with a high degree of reliability. The processing and interpretation of bile drainage specimens is not standardized, and the sensitivity of SBD is less than that of endoscopic ultrasound (EUS). Combined endoscopic ultrasound and stimulated biliary drainage (EUS/SBD) offers a high degree of sensitivity in the diagnosis of cholecystitis and microlithiasis. Positive EUS/SBD is also highly correlated with long-term symptom resolution or relief following cholecystectomy.