The 17th century London neuroanatomical school headed by Thomas Willis provided us with the first identifiable images of the sympathetic nervous system. Nineteenth century giants of European physiology (Bernard, Waller, Brown-Sequard) identified these as the “pressor nerves”. Von Euler’s demonstration that the sympathetic transmitter was noradrenaline brought the field into the modern era. With the development of contemporary techniques for recording from human sympathetic nerves and quantifying rates of noradrenaline release, the sympathetic nervous system became accessible to clinical scientists investigating possible contributions to cardiovascular and other diseases. Sympathetic nervous system responses typically are regionally differentiated, activation in one outflow sometimes accompanying no change or sympathetic inhibition in another. Regional sympathetic activity is best studied in humans by recording from postganglionic sympathetic efferents (multiunit or single fiber recording) and by isotope dilution-derived measurement of organ-specific noradrenaline release to plasma (regional ‘noradrenaline spillover”). With the application of these techniques, evidence has been assembled in the past three decades which indicates that sympathetic nervous system abnormalities are crucial in the development of cardiovascular disorders, notably heart failure, essential hypertension, disorders of postural circulatory control causing syncope, and “psychogenic heart disease”, heart disease attributable to mental stress and psychiatric illness. These abnormalities involve persistent, adverse activation of sympathetic outflows to the heart and kidneys in heart failure and hypertension, episodic or ongoing cardiac sympathetic activation in psychogenic heart disease and defective sympathetic circulatory reflexes in disorders of postural circulatory control. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this “mechanisms to management” transition is at differing stages of development with the different conditions. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to introduction of beta-adrenergic blockers, an effective therapy. With psychogenic heart disease and postural syncope syndromes, knowledge of the neural pathophysiology is emerging, but clinical translation remains for the future. Perhaps we are on the cusp of effective translation in patients with essential hypertension, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on prior demonstration in them of activation of the renal sympathetic outflow.