Clinical Scenario: Resistance training (RT) programs promote skeletal muscle hypertrophy through the progressive physiological stress applied to an individual. Currently, the vast majority of studies regarding the hypertrophic response to RT have focused on either sedentary or untrained individuals. This critically appraised topic focuses on the hypertrophic response to high- and low-load RT in resistance-trained men. Clinical Question: In experienced male weightlifters, does high-load RT lead to greater increases in muscle mass than low-load RT? Summary of Key Findings: Six studies met the inclusion criteria, while 4 studies were included in the analysis. Each of the 4 studies showed that low-load RT elicited hypertrophic gains similar to high-load RT when sets were taken to failure. Three of the studies were not volume equated, indicating a dose–response relationship between training volume-load and skeletal muscle hypertrophy. One of the studies was volume equated, indicating that skeletal muscle hypertrophy could be achieved at levels comparable to those observed in high-load protocols as a result of high levels of metabolic stress and the concomitant recruitment of high-threshold motor units that can occur during fatiguing contractions. Clinical Bottom Line: Evidence suggests that low-load training produces hypertrophic gains similar to those observed in high-load RT protocols when sets are taken to failure in resistance-trained men. Strength of Recommendation: There is moderate to strong evidence to suggest that low-load RT elicits hypertrophic gains similar to those observed in high-load RT protocols when sets are taken to failure in resistance-trained men.