Static isometric exercise increases muscle sympathetic nerve activity (MSNA) and mean arterial pressure, both of which can be maintained at the conclusion of the exercise by occlusion of the arterial supply [postexercise ischemia (PEI)]. To identify the cortical and subcortical sites involved, and to differentiate between central command and reflex inputs, we used blood oxygen level-dependent (BOLD) functional MRI (fMRI) of the whole brain (3 T). Subjects performed submaximal static handgrip exercise for 2 min followed by 6 min of PEI; MSNA was recorded on a separate day. During the contraction phase, parallel increases in BOLD signal intensity occurred in the contralateral primary motor cortex and cerebellar nuclei and cortex; these matched the effort profile and ceased at the conclusion of the contraction. Progressive increases in the contralateral insula and primary and secondary somatosensory cortices, with progressive decreases in the perigenual anterior cingulate and midcingulate cortices, were sustained during the period of PEI and thus did not depend on central command. Discrete bilateral activation of the medial and lateral dorsal medulla was also observed during the contraction and PEI; we believe that these represent the nucleus tracts solitarius (NTS) and rostral ventrolateral medulla (RVLM), respectively. Given that metaboreceptor afferents are known to project to the NTS and that the RVLM is the primary output nucleus for MSNA, our data support that the metaboreflex is mediated by the medulla, whereas the somatosensory, insular, and anterior cingulate cortices are involved in the sensory and affective components of the maneuver.