This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5-HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction. In fact, transgenic approaches have revealed that adult cardiac status is strongly influenced by maternal serotonin. Serotonin has long been known to be a vasoconstrictor in adult physiology. Analysis of animals knocked-out for the serotonin transporter suggested a role in blood pressure control and revealed an effect of 5-HT(2B) receptor antagonists in hypertension. In the lung vasculature, mice lacking the 5-HT(2B) receptor gene that are exposed to chronic hypoxia are resistant to pulmonary hypertension, while 5-HT(1B) receptor and serotonin transporter mutant animals show partial resistance. In platelets, mutant mice revealed that serotonin transporter regulates not only the mechanisms by which serotonin is packaged and secreted but also platelet aggregation. Studies looking at adult cardiac remodeling showed that mice lacking the 5-HT(2B) receptor gene were protected from cardiac hypertrophy. Their fibroblasts were unable to secrete cytokines. Crossing these animals with mice overexpressing the receptor in cardiomyocytes revealed the contribution of cardiac fibroblasts and 5-HT(2B) receptors to cardiac hypertrophy. In mice lacking the monoamine oxidase-A gene, the role of serotonin degradation in cardiac hypertrophy was confirmed. Works with gene-modified animals has contributed strongly to the re-evaluation of the influence of serotonin on cardiovascular regulation, though several unknowns remain to be investigated.