Despite the growing interest in Paralympic sport, the evidence base for supporting elite wheelchair sport performance remains in its infancy when compared with able-bodied (AB) sport. Subsequently, current practice is often based on theory adapted from AB guidelines, with a heavy reliance on anecdotal evidence and practitioner experience. Many principles in training prescription and performance monitoring with wheelchair athletes are directly transferable from AB practice, including the periodization and tapering of athlete loads around competition, yet considerations for the physiological consequences of an athlete’s impairment and the interface between athlete and equipment are vital when targeting interventions to optimize in-competition performance. Researchers and practitioners are faced with the challenge of identifying and implementing reliable protocols that detect small but meaningful changes in impairment-specific physical capacities and on-court performance. Technologies to profile both linear and rotational on-court performance are an essential component of sport-science support to understand sport-specific movement profiles and prescribe training intensities. In addition, an individualized approach to the prescription of athlete training and optimization of the “wheelchair–user interface” is required, accounting for an athlete’s anthropometrics, sports classification, and positional role on court. In addition to enhancing physical capacities, interventions must focus on the integration of the athlete and his or her equipment, as well as techniques for limiting environmental influence on performance. Taken together, the optimization of wheelchair sport performance requires a multidisciplinary approach based on the individual requirements of each athlete.