Beta-blockers are prescribed for a variety of cardiovascular conditions including hypertension, heart failure, primary treatment of myocardial infarction (MI), and secondary prevention of ischemic cardiac events. Yet they remain underprescribed in populations at increased risk for cardiovascular disease because of tolerability and safety concerns. Beta-blockers are heterogeneous with respect to pharmacokinetic and pharmacodynamic effects. "Original" agents were nonselective, blocking both beta1-adrenoceptors and beta2-adrenoceptors. Later, new agents were developed with selectivity for beta1-adrenoceptors, and were subsequently followed by beta-blockers, which exhibit additional effects, such as vasodilation. Among newer agents, labetalol, carvedilol, and nebivolol have been approved for use in the United States. Nebivolol possesses both beta1-selectivity and nitric oxide-mediated vasodilatory effects, while carvedilol has attractive effects on insulin resistance and exhibits antioxidant effects. Newer beta-blockers may overcome concerns about efficacy, adverse effects, and tolerability, while delivering cardiovascular protection.