Stroke is a leading cause of permanent impairments among its survivors. Although patients need to go through intensive, longitudinal rehabilitation to regain function before the stroke, patients show poor engagement and adherence to rehabilitation therapies which hampers their recovery. As a means to enhance stroke survivors' motivation, engagement, and adherence to intensive and longitudinal rehabilitation, the use of games in stroke rehabilitation has received attention from research and clinical communities. In order to realize this, it is important to take a holistic, end-to-end research approach that encompasses 1) the development of game technologies that are not only entertaining but also rehabilitating or monitoring the functional/impairment level, 2) the quantitative evaluation of the clinical efficacy of the technologies, and 3) the deployment of the technologies in real-world clinical settings to understand if the anticipated clinical efficacy is achieved and how the technologies affect the interaction dynamics among patients, therapists and the technologies. In this dissertation, we introduce our approach to this holistic, end-to-end research for the development, validation, and understanding of real-world use of games in stroke rehabilitation. Towards that end, we designed and developed Neuro-World that can enable accurate, longitudinal assessment of patients' cognitive function outside the clinical setting. The analysis results in the controlled setting show that the proposed approach can accurately assess patients' cognitive function without the help of therapists. While it remains as a future study to deploy Neuro-World in stroke survivors' free-living environments and study the system's impacts on patients' engagement patterns, we use another game platform (i.e., RAPAEL Smart Board) to demonstrate our efforts to understand the real-world interaction dynamics. We investigate the use of the games in the actual hospital setting where the system has been adopted as part of stroke survivors' routine upper-limb motor rehabilitation therapies. Our findings reveal patients’ unexpected engagement patterns, therapists’ critical roles and challenges in maintaining patients' engagement and therapeutic value. These findings enhance our understanding of the impact of serious games on the patients' engagement to rehabilitation therapies and provide us with insights into potential directions leading to the development of more effective games for stroke rehabilitation.