Several important problems in the majority of industrialized countries have challenged the centralized and overburdened current model of healthcare. Telehealthcare systems are presented as a new paradigm, offering high expectations to provide effective solutions to this picture. With this paper we present a new methodological approach for telehealthcare systems that pursues the generation of clinical and physiological knowledge of the patient in a real time and personalized manner. This approach is based on a computational component, identified as patient physiological image (PPI), which is responsible for generating an image of the state of the patient and therapy devices. Three key issues of the proposed methodological approach are evaluated. With the objective to validate the capability of the PPI to determine the internal state of a patient, a digital simulation experiment over the mathematical model of a PPI is done. Numerical results are compared to those obtained by a validated mathematical model. Secondly, a laboratory prototype of a novel human physical activity monitor that follows the designed methodological approach will be tested, in order to evaluate the trade‐off between processing capacity, portability, and cost‐efficiency and power consumption, which are necessary to assure its compliance with the methodology. As a third key issue, the capability of our methodology to integrate physiological information belonging to different scales is analyzed. This is done by means of a case study related to the integration of the regulation of water function of AQP2 channels (genomic, proteomic and cellular levels) into a kidney collecting duct epithelium mathematical model of a PPI. The analysis and preliminary evaluation of the proposed telehealthcare methodological approach, featured by an advanced personalization of health assistance, have been satisfactory.