Providing sedation for patients undergoing gastrointestinal (GI) endoscopy continues to be a debated topic in both anesthesia and gastroenterology circles. Sedation approaches are widely varied across the globe. While propofol administration is embraced by more endoscopists and patients, its administration evolves controversy. Whereas trained nurses and gastroenterologists are allowed to administer propofol for GI endoscopy sedation in Europe and Asia, it is the sole privilege of anesthesia providers in the USA. However, the costs of anesthesia providers are significant and threaten to derail the screening colonoscopy practice. Efforts were made by both drug and device manufacturers to find alternatives. Fospropofol was one such effort that did not live up to the expectations due to respiratory depressant properties that were similar to propofol. Use of a new tool to administer propofol in the form of Sedasys® was the next experiment that tried to find alternative to anesthesia providers. The device did not succeed due to inadequate sedation. The latest effort is remimazolam, a new benzodiazepine that has quicker recovery profile. In the interim, many drug combinations such as propofol–dexmedetomidine and propofol–ketamine are improving the safety without compromising the quality of sedation. This review attempts to discuss the new drug innovations and drug combinations of existing sedatives for the benefit of readers.