Obesity has reached epidemic proportions worldwide. Sympathetic nervous system activation has been shown to play a major role linking obesity to the development of associated metabolic complications, such as hypertension. Recent evidence has implicated central melanocortin signalling in the regulation of blood pressure in rodents and humans. The importance of sympathetic neural activity in mediating this association has been highlighted. Humans with loss‐of‐function mutations in the melanocortin 4 receptor (MC4R) are an ideal group of subjects in whom the importance of melanocortin signalling in linking obesity to hypertension can be studied. Consistent with rodent studies, it was recently demonstrated that humans with MC4R deficiency have lower blood pressure, less hypertension, lower 24‐h urinary catecholamine excretion, lower resting heart rate and attenuated insulin‐mediated sympathetic activation compared to equally‐obese humans. In overweight and obese humans without MC4R mutations, the infusion of a highly‐selective MC4R agonist led to dose‐dependent increases in blood pressure and heart rate. All effects were independent of insulin. This evidence supports the notion that the melanocortin system regulates blood pressure and sympathetic neural function. The results obtained in rodent and human studies, in relation to blood pressure and sympathetic function, may limit the use of MC4R agonists for the treatment of obesity. Future studies will determine whether MC4R deficiency is associated with protection from development of the detrimental cardiovascular consequences that accompany obesity.