Purpose: To outline the potential mechanisms and experimental limitations for exercise-induced pain inhibition. Methods: Investigations that applied physical exertion to evoke changes in experimental pain response were reviewed and evaluated for inclusion. Previous research studies were appraised in a historical context to explicate pain measurement and to expound the prospective underlying mechanisms for exercise-induced pain inhibition. Results: The function of pain-modulatory systems during exercise may have evolved to extend performance and survival. Previous studies have implicated the modulation of pain through activation of descending inhibitory pathways and attenuation of ascending pain-related signaling during and after physical exercise. Central and peripheral release of compounds, such as endorphins and endocannabinoids, as well as baroreceptor inhibitory effects on pain have been postulated in exercise-induced pain inhibition. Inhibition of pain with exercise appears to show adaptation, as revealed by enhanced tolerance to pain with exercise training. Conclusion: The diminution of pain with physical exercise has been associated with mediation of pain-related signaling at central and peripheral sites. Application of this finding could extend into human performance and the therapeutic treatment of pain.