Blood flow restriction (BFR) resistance training has demonstrated its effectiveness for inducing hypertrophic adaptations at much lower intensities (20-30% one-repetition maximum (1RM)) compared to traditional high-intensity (>65% 1RM) recommendations. Limited research has examined BFR in conjunction with high-intensity resistance training, with mixed results. The purpose of this dissertation was to expand upon this understudied area with a series of three studies to 1) better understand blood flow responses in the lower limbs with varying occlusion pressures, 2) determine the effect of high-intensity BFR (HI-BFR) resistance exercise on fatigue, ratings of perceived exertion (RPE), and pain, and 3) examine the influence of HI-BFR on metabolic stress, muscle damage, and hypoxia. Study 1 examined the effects of varying BFR occlusion pressures on blood flow volume in the legs. Results indicate a potential 50% limb occlusion pressure (LOP) threshold at which point statistically significant reductions in blood flow volume occur in the posterior tibial artery. An observed plateau in blood flow reductions between 60-80%LOP indicates the potential for reduced occlusion pressure during exercise. Study 2 examined the effects of HI-BFR on inter-set fatigue, RPE, and Pain, in addition to post-exercise neuromuscular fatigue/impairment. Significantly greater number of total repetitions and repetitions during sets 1, 2, and 4 (p < .05) were performed in the CTRL condition. Although RPE between conditions was similar across all sets (p ≥ .05), perceived pain was significantly greater in BFR across all sets (p < .05). Changes in neuromuscular performance measures were consistent across exercise conditions. Study 3 investigated the effect of HI-BFR on metabolic stress, muscle swelling, and muscle damage in response to a back-squat protocol. Significantly lower blood lactate concentrations were measured following the BFR exercise stimulus, compared to CTRL (p = .001). No significant differences in muscle swelling were observed between conditions. Post-exercise interleukin-6 was significantly greater following the BFR exercise (p = .007). The use of BFR during high-intensity resistance exercise seems to be a useful method for advanced induction of fatigue during exercise, although the reduced exercise volume due to fatigue and pain limits the overall acute hypertrophic mechanistic responses.