It is generally thought that exercise is beneficial to alleviate pain. However, prolonged movement may lead to the development of painful injuries, because of the overload of low-threshold motor units. Especially in individuals with a pain condition, exercise prescription and the impact of fatigue is less clear. This may be because of the dual effects, aggravation and relief, which fatigue has on pain. The purpose of this review is to ascertain the relation between pain and the motor system, both in the development and management of pain. Recent studies show that fatigue alters pain-induced increases in corticomotor excitability and leads to within and between-muscle adaptations. Studies of acute pain have shown complex adaptations such as increased movement variability, which may be because of a search for motor solutions to prolong overall task performance. In contrast, chronic pain seems to limit movement duration, speed, and variability which could be protective in the short term but also counterproductive over time. Owing to these adaptations in movement strategies, pain chronicity may help to dictate exercise prescription. For example, the correct dosage of multimuscle, dynamic exercises would act to promote movement variability. Thus, it seems that exercise involving the use of different movement strategies could be effective in helping people to obtain exercise-induced benefits while avoiding injury and pain reaggravation.