Purpose: Afferent input from exercising muscle reflexively increases muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP), both of which can be maintained at the conclusion of the exercise by occlusion of the arterial supply (post-exercise ischaemia, PEI). Using fMRI, we have recently shown that inspiratory apnoea is accompanied by increases in MSNA and insular cortex activation. To test whether MSNA output and insular activation are directly related, we hypothesized that the insular cortex is also activated during metaboreflex engagement. Methods: Subjects (n = 17) performed static handgrip (SHG) for 2 min (40% MVC), followed by 6 min of PEI. fMRI signal intensity changes (gradient echo) were measured using a 3T scanner (Philips). 240 volumes (42 axial slices, TR=3 s, TE=30 ms, flip angle=90 deg, raw voxel size=1.8x1.8x3mm) were collected. Significant changes in fMRI signal intensity (SPM2, random effects, corrected p < 0.01) were determined on a voxel-by-voxel basis, using a box-car model. On a separate day MSNA by microneurography and MAP were recorded during the same protocol in the same subjects. Results: SHG and PEI caused increased MSNA (202 ± 24% of baseline) and MAP (+17 ± 3mmHg); a robust activation of the left (contralateral) insula (3.0 ± 0.2%) and bilateral activation of the rostral ventrolateral medulla (1.1 ± 0.3%). Conclusions: The insular cortex is activated during at least two different sympathoexcitatory reflexes, apnoea and the metaboreflex. Thus, the insular cortex may exert important 'higher' regulatory control of brainstem sympathetic outflow. Furthermore the resolution of fMRI now allows imaging insight into activation of human brainstem vasomotor centers.