The regulation of the heart and peripheral circulation by the nervous system is accomplished by control centers in the medulla that receive descending input from higher neural areas in the brain and afferent input from mechanically and chemically sensitive receptors located throughout the body. The resultant changes in efferent sympathetic and parasympathetic activity allow rapid cardiovascular responses during a number of physiological perturbations including changes in posture, physical activity, temperature, altitude, and microgravity. The ability to record sympathetic nerve activity targeted to the skeletal muscle vasculature with intraneural microelectrodes has provided a powerful new tool to study fundamental mechanisms of neurocirculatory regulation in conscious human subjects. In the last three decades, microneurographic studies have shed new light on the reflex regulation of skeletal muscle sympathetic nerve activity by arterial baroreceptors, arterial chemoreceptors, and cardiopulmonary baroreceptors. In addition, microneurography is particularly well suited to study the regulation of muscle sympathetic nerve activity by skeletal muscle afferents and central neural drive (central command) during static exercise. This review highlights the experimental approaches using microneurography and some new conclusions concerning regulation of sympathetic nerve activity to the human skeletal muscle bed.