Blood flow restriction (BFR) alone or in combination with exercise has been shown to result in favorable effects on skeletal muscle form and function. The pressure applied should be high enough to occlude venous return from the muscle but low enough to maintain arterial inflow into the muscle. The optimal pressure for beneficial effects on skeletal muscle are currently unknown; however, preliminary data from our laboratory suggests that there may be a point where greater pressure may not augment the response (e.g. metabolic accumulation, cell swelling) but may actually result in decrements (e.g. muscle activation). This led us to wonder if BFR elicits somewhat of a hormesis effect. The purpose of this manuscript is to discuss whether pressure may be modulated to maximize skeletal muscle adaptation with resistance training in combination with BFR. Furthermore, the potential safety issues that could arise from increasing pressure too high are also briefly reviewed. We hypothesize that with BFR there is likely a moderate (∼50% estimated arterial occlusion pressure) pressure that maximizes the anabolic response to skeletal muscle without producing the potential negative consequences of higher pressures. Thus, BFR may follow the hormesis theory to some degree, in that a low/moderate dose of BFR produces beneficial effects while higher pressures (at or near arterial occlusion) may decrease the benefits of exercise and increase the health risk. This hypothesis requires long term studies investigating chronic training adaptations to differential pressures. In addition, how differences in load interact with differences in pressure should also be investigated.