Sympathetic nerves play a pivotal role in control of systemic vascular resistance and autonomic regulation of arterial blood pressure. Furthermore, microneurography, the technique for recording neural activity directly from peripheral nerves innervating skeletal muscle vessels, is a fundamental tool for studying sympathetic modulation of vascular resistance and blood pressure during a variety of physiological and environmental challenges. During a bout of vigorous exercise, increased muscle sympathetic nerve activity (MSNA) and ensuing vasoconstriction in contracting muscle avert a drop in arterial blood pressure and vital perfusion when metabolic vasodilation would otherwise threaten to outstrip the pumping capacity of the heart. Notably, increased sympathetic outflow to skeletal muscle vasculature during exercise arises from integration of multiple neural inputs to the lower brainstem, including central command, afferent feedback from contracting muscle, and the arterial baroreceptors. In healthy individuals, it is apparent that exercise training can lead to heightened basal MSNA and resetting of the vascular sympathetic baroreflex, adjustments that might be important for maintaining arterial blood pressure in the face of cardiac and vascular adaptation induced by years of athletic training. Exposure to high altitude (HA) hypoxia is another physiological state in which skeletal muscle vasodilation challenges sympathetic modulation of vascular resistance and arterial blood pressure. Although relatively few in number, microneurographic studies indicate that heightened MSNA is a feature of HA exposure, not only in lowland natives, but also in highland populations who have generational exposure to ambient hypoxia. This invited talk will explore mechanisms underpinning the sympathetic neural adaptive responses to exercise in health and compare these with alterations in sympathetic outflow that are a feature of altitude acclimatization and adaptation.