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This paper addresses research development regarding the adoption of natural user interfaces (NUI) in the Serious Games for Rehabilitation area of application. From previous studies, we identified as a research opportunity the potential benefits of the adoption of more natural interaction modalities. This paper describes the main problems and how serious games and NUI can benefit the process of rehabilitation. We describe our recent work on this subject, including the design of a game prototype using alternative (in respect to the conventional WIMP) interaction. We conducted a playability study in order to make it possible to evaluate and measure the benefits of the newer forms of interaction. From the results study, we concluded that the introduction of the natural interaction modalities has increased the attractiveness and intuitiveness of the prototyped Serious Game. Lastly, we report some conclusions and identify research opportunities and open problems in this area.