Superior capsular reconstruction has received increased attention as a surgical technique to address massive "irreparable" rotator cuff tears; however, the functional limitations and surgical techniques associated with this repair have yet to be sufficiently explored. The goal of this study was to utilize a multidisciplinary approach to characterize the biomechanics of this repair by: (i) identifying activities of daily living that may overburden the graft; and (ii) optimizing surgical techniques used during implantation. This experiment was completed in three phases. First, graft failure mechanics were characterized by performing an in vitro experiment. Second, in vivo shoulder kinematics associated with various activities were recorded with 3-D motion capture techniques. Finally, an in silico model was used to assess graft strains. Results show that motions involving posterior shoulder rotation, such as back washing, lead to graft strains that may cause failure. Output from the optimization suggests that orienting the humerus in approximately 25° abduction, and 20° internal rotation during implantation will result in optimal graft performance. Clinical Significance: The novel paradigm used in this study demonstrates the utility of coupling in vitro, in vivo, and in silico modeling techniques in one cohesive experiment. This paradigm presents an additional tool, aside from clinical studies and cadaveric experimentation, to better predict and understand the strengths and limitations of superior capsular reconstruction. This approach has potential to be translated to other soft tissue repairs and may provide valuable information to clinicians and rehabilitative specialists to manage patient expectations and guide rehabilitation. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2789-2796, 2018.