There are now 3 classes of ß-blockers available for clinical use. Table 2 gives the adrenergic receptor blocking profiles for selected ß-blocking agents, including those that have been widely used in heart failure clinical trials. Propranolol is the prototype nonselective compound, introduced into clinical practice in 1968 as an antianginal agent. Propranolol and other “first-generation” compounds, such as timolol, are nonselective agents with equal affinities for blocking ß1 and ß2 receptors and no important pharmacological properties other than ß-blockade. In the 1970s, pharmaceutical companies developed “cardioselective” or second-generation ß-blockers that selectively antagonized ß1-compared with ß2-receptors. This was done in the mistaken belief10, 11 that the human heart could be selectively ß-blocked, on the basis of data from animal models in which only ß1-receptor–mediated responses were identified in the myocardium. It was hoped that a lack of ß2-receptor blockade would also reduce some of the perceived peripheral and pulmonary side effects of ß-blockers, a hypothesis that also was never conclusively proved. The first truly selective ß1-blocking agent was practolol, 31 which was sufficiently ß1-selective that it could be used along with propranolol to demonstrate 3 distinct subtypes (ß1, ß2, and ß3) of ß-adrenergic receptors, 32 which were ultimately shown to be the products of 3 distinct genes. 33–35 Practolol was also the first ß-blocking agent to be therapeutically administered by the pioneering Goteborg group to a patient with chronic heart failure. 36 Ultimately, practolol was removed from clinical practice because of immunological adverse effects and was replaced by metoprolol in the Goteborg studies. As shown in Table 2, metoprolol is approximately 75-fold selective for human ß1-versus ß2-receptors. In the 1980s, pharmaceutical companies developed even more ß1-selective compounds, such as bisoprolol, which is 120-fold selective (Table 2). As discussed below, both metoprolol and bisoprolol have been used extensively in heart failure trials and both have recently been shown to reduce mortality in phase 3 clinical trials. 37, 38