Despite our environment is often uncertain, we generally manage to generate stable motor behaviors. While reactive control plays a major role in this achievement, proactive control is critical to cope with the substantial noise and delays that affect neuromusculoskeletal systems. In particular, muscle co-contraction is exploited to robustify feedforward motor commands against internal sensorimotor noise as was revealed by stochastic optimal open-loop control modeling. Here, we extend this framework to neuromusculoskeletal systems subjected to random disturbances originating from the environment. The analytical derivation and numerical simulations predict a singular relationship between the degree of uncertainty in the task at hand and the optimal level of anticipatory co-contraction. This prediction is confirmed through a single-joint pointing task experiment where an external torque is applied to the wrist near the end of the reaching movement with varying probabilities across blocks of trials. We conclude that uncertainty calls for impedance control via proactive muscle co-contraction to stabilize behaviors when reactive control is insufficient for task success.Author summaryThis work presents a computational framework for predicting how humans modulate muscle co-contraction to cope with uncertainties of different origins. In our neuromusculoskeletal system, uncertainties have both internal (sensorimotor noise) and external (environmental randomness) origins. The present study focuses on the latter type of uncertainty, which had not been dealt with systematically previously despite its importance in everyday life. Therefore, we thoroughly investigated how random disturbances occurring with some probability in a motor task shape the feedforward control of mechanical impedance through muscle co-contraction. Here we provide theoretical, numerical and experimental evidence that the optimal level of co-contraction steeply increases with the uncertainty of our environment. These findings show that muscle co-contraction embodies uncertainty and optimally mitigates its consequences on task execution when feedback control is insufficient due to sensory noise and delays.