Restlessness examinations necessitate an inclusive viewpoint, which considers factors, e.g., sensory processing dysfunctions, (dis)comfort and pain, in an environmental context. Therefore, extending the spectrum of behavioral semiology for disruptive daytime behaviors to capture hypermotor-restlessness will allow a functional 360-degree approach to the affected individual. We propose the development of an evidence-based intervention program for children, youth and young adults that: (i) is co-developed by patients, providers, and methodologists and will address restless sleep and wake behaviors; (ii) focuses on key questions regarding the comparative effectiveness of new and existing treatments, as it will capture restlessness in a novel and structured way; (iii) is based on and contributes to robust evaluation methods, allowing each individual to be treated in a customized or personalized way; and (iv) establishes a research infrastructure that can be leveraged in a timely and coordinated manner to pursue research questions as they emerge from the disciplines involved. We will utilize innovative and unique technologies and analysis algorithms for in-depth phenotyping via neuroanatomy and neurophysiology. Patient-reported outcome measures and data will support this in-depth phenotyping endeavor, and will also create a novel deeper layer to disease management and allow the personalization of treatment at a ‘precision medicine’ level. Thus, this research endeavour opens a new concept of interaction with patients with a high burden of suffering using mutual respect and without tokenism or labeling.