beta-Arrestin1 knockout mice were studied to define the physiological role of beta-arrestin1 in the regulation of G protein-coupled receptors. beta-Arrestin1 is thought to be involved in the desensitization of many G protein-associated cell surface receptors, particularly beta-adrenergic receptors. Homozygous knockout mice are overtly normal. Resting cardiovascular parameters modulated by beta-adrenergic receptors such as heart rate, blood pressure, and left ventricular ejection fraction are not changed. However, homozygous mutants are more sensitive to beta-receptor agonist-stimulated increases in ejection fraction, consistent with a role of beta-arrestin1 in beta-adrenergic receptor desensitization. We conclude that beta-arrestin1 is important for in vivo G protein-coupled receptor desensitization and that this aspect of desensitization represents a mechanism for fine-tuning responses. However, beta-arrestin1 does not appear to be required for development or for other essential biological functions.