Individuals with neuromuscular pathologies are often prescribed an ankle-foot orthosis (AFO) to improve their gait mechanics by decreasing pathological movements of the ankle and lower limb. AFOs can resist or assist excessive or absent muscular forces that cause tripping, instability, and slow inefficient gait. However, selecting the appropriate AFO with mechanical characteristics that limit pathological ankle motion in certain phases of the gait cycle, but allow the ankle to move effectively during other phases requires detailed clinical decision-making. The aim of this study is to propose an explicit methodology for the adjustment of Multi-Function articulated AFOs in the clinical setting. A secondary aim is to present the evidence upon which this method is based and to identify gaps in that evidence as opportunities for future research. An emerging class of AFO, the Multi-Function articulated AFO offers features that permit more comprehensive, iterative, and reversible adjustments of AFO ankle alignment and resistance to ankle motion. However, no standard method exists for the application and optimization of these therapeutic devices in the clinical setting. Here we propose an evidence-based methodology applicable to the adjustment of Multi-Function articulated AFOs in the clinical setting. Characteristic load-deflection curves are given to illustrate the idealized, complex resistance-angle behavior of Multi-Function articulated AFOs. Research is cited to demonstrate how these mechanical characteristics can help to ameliorate specific pathologic ankle and knee kinematics and kinetics. Evidence is presented to support the effects of systematic adjustment of high resistance, alignable articulated AFOs to address many of the typical pathomechanical patterns observed in individuals with neuromuscular disorders. Published evidence supporting most decision points of the algorithm is presented, and gaps in that evidence are identified. Finally, two hypothetical case examples are given to illustrate the application of the method to the optimization of articulated AFOs treating specific gait pathomechanics. This method is proposed as an evidence-based systematic approach for the adjustment of Multi-Function articulated AFOs, using observed gait deviations mapped to specific changes in AFO alignment and resistance settings as a clinical tool in the orthotic treatment of individuals with complex neuromuscular gait disorders.