Endoscopic sphincterotomy is performed on the biliary and pancreatic sphincters for a variety of indications such as removal of stones, as part of treatment of strictures, to facilitate placement of stents, for closure of ductal leaks, and other indications. Pancreatic sphincterotomy has been increasingly performed for the treatment of papillary stenosis, sphincter of Oddi dysfunction, and for chronic and acute recurrent pancreatitis. Efficacy is clear for more traditional indications, but is not as well defined for some of the latter indications. Minor papillotomy is most often performed for acute recurrent pancreatitis associated with pancreas divisum, sometimes for chronic pancreatitis, and for other indications. Equipment, techniques, and safety of sphincterotomy have improved significantly over the past decades. Success rates are substantially higher when a sphincterotomy is performed by high-volume endoscopists. However, complications such as pancreatitis, bleeding, and perforation can still occur in up to 10% of cases and may occasionally be severe. Patients with the least clear indication or chance of benefit from sphincterotomy, such as those with suspected sphincter of Oddi dysfunction or suspected but absent bile duct stones, are at highest risk of complications. Complications are less frequent, but fully not eliminated, with an experienced endoscopist or an expert in the field. Risk of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) with biliary and/or pancreatic sphincterotomy can be substantially reduced by placement of a small-caliber pancreatic stent. Major challenges include defining the settings in which sphincterotomy is most likely to be effective, selection of appropriate patients for therapeutic ERCP by utilization of alternative imaging techniques such as magnetic resonance cholangiopancreatography and endoscopic ultrasound, and dissemination of newer techniques into practice to ensure optimal safety and efficacy for sphincterotomy.