Ideas about the relative importance of the autonomic nervous system in blood pressure (BP) regulation come and go. Fortunately, the actions of the autonomic nervous system are not so fickle and when this system works well, BP is regulated in a fairly narrow (but not constant) range at rest and is also able to rise and fall ‘appropriately’ to meet the demands of various forms of mental, emotional and physical stress. Both the tight regulation of BP and the ability to reset that regulation to meet variable demands on the system are lost when the autonomic nervous system is absent or when key feedback mechanisms that govern it are destroyed. The 2007 Michael de Burgh Daly lecture will highlight the evolution of our ideas about the autonomic nervous system in the context of BP regulation as general thinking about human normotension emerges from the relatively ‘renal-centric’ era of the last ~30 years. The lecture will focus specifically on the idea that there is a high degree of inter-individual variability in key elements of the autonomic nervous system and the responses they govern. This variability is somehow balanced in normotensive individuals so that it has minimal effects on BP. For example, the vasoconstrictor responses to alpha-adrenergic agonists (including post-junctional alpha-2 receptors) can vary 2- to 3-fold among normotensive young subjects and adrenergic sensitivity declines with healthy ageing. There is even greater variability in sympathetic neural activity in normotensive individuals. Resting muscle sympathetic nerve activity (MSNA) is reproducible in individuals, but can vary as much as 10-fold among individuals with similar blood pressures. However, MSNA has a reciprocal relationship with both cardiac output (CO) and adrenergic responsiveness that seems to keep BP ‘normal’ in humans who have high sympathetic neural outflow. The relationships among these factors (CO, MSNA and adrenergic sensitivity) and indices of baroreflex function are providing clues and generating questions about how this variability is integrated to regulate BP in a coherent way. Key questions include: 1) What is the biological basis of the variability in key sub-systems? 2) How are the balances among adrenergic responsiveness, MSNA and individual hemodynamic patterns coordinated in normotension? 3) How might dysfunction or imbalance between and among elements of the autonomic nervous system contribute to disease? 4) Finally, are there larger population-based consequences related to variability in the autonomic nervous system that might have implications for public health? By addressing these issues and raising these questions the hope is to be more provocative than correct, emphasize the implicit limits of reductionism, and highlight continuing relevance of studying the alive awake human.