In this study, we investigated central/supraspinal processes mediating cessation of a muscle fatiguing exercise. Fifteen male subjects performed 39 intermittent, isometric handgrip contractions (13 s on, 5–6 s off) with the dominant right hand while brain activation was assessed by means of functional magnetic resonance imaging (fMRI). An adaptive, partly stochastic protocol was designed such that in approximately 50% of the contraction trials the required force could not be held until the end of the trial (task failure trial). Trials performed in compliance with the force requirements (succeeded trial) were compared with task failure trials concerning neural activity during a small time window before task failure occurred. The data revealed significantly increased activation contralaterally in both the mid/anterior insular cortex and the thalamus during the investigated time window in the case of subsequent task failure. In accordance with other studies investigating sensations that alert the organism to urgent homeostatic imbalance such as air hunger, hunger for food, and pain, we assume that an increased thalamo-insular activation in the context of a fatigue-induced handgrip exercise could reflect increased homeostatic disturbance in the exercising muscle and may be of essential importance by mediating task failure to maintain the integrity of the organism. Hum Brain Mapp, 2011. © 2010 Wiley Periodicals, Inc.