β-Blockers are useful drugs in several clinical cardiologic scenarios. Their use in the perioperative period and in critically ill patients is increasing, but their effect on clinically relevant outcomes remains controversial. Long-acting β-blockers can have detrimental effects that are difficult to be counteracted in these settings. The authors describe the possible clinical uses of ultra-short–acting β-blockers (esmolol and landiolol) in the perioperative period and in critically ill patients because these drugs have the beneficial effects of β-blockers, but do not have the detrimental effects of long-acting agents. This narrative review focuses on ultra-short–acting β-blockers in the following clinical settings: prevention and treatment of arrhythmias and myocardial ischemia in noncardiac and cardiac surgery, usage as cardioplegia adjuvants or to test the reversibility of systolic anterior motion of the mitral valve in cardiac surgery, medical treatment of aortic dissection before surgery, improvement of microcirculation and oxygenation in critically ill patients experiencing sepsis or undergoing extracorporeal membrane oxygenation, anesthesia induction, and coronary computed tomography angiography. © 2017 Elsevier Inc.