Advances in technology and improvement of efficacy for many neuromodulation applications have been achieved without understanding the relationship between the stimulation parameters and the neural activity which is generated in the nervous system. It is the neural activity that ultimately drives the therapeutic benefit and the advent of evoked compound action potential recording allows this activity to be directly measured and quantified. Closed-loop control adjusts the stimulation parameters to maintain a predetermined level of neural recruitment and has been shown to provide improved pain relief in individuals with spinal cord stimulators. However, no mechanism that relates more consistent neural recruitment to patient outcomes has been proposed. The authors propose a hypothesis that may explain the difference in efficacy between open- and closed-loop operational modes by considering the relationship between measured neural recruitment with hypothetical dose and side effect response curves. This provides a rational basis for directing clinical research and improving therapeutic systems.