α-Calcitonin gene-related peptide (αCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of αCGRP, we developed an αCGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained αCGRP-null mice than in corresponding wild-type mice. The elevated MAP in αCGRP-null mice was shown to be the result of elevated peripheral vascular resistance by α-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between αCGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in αCGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that αCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.