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Key links of arterial hypertension (AH) pathogenesis, like many other diseases of complex etiology, remain unknown, and its palliative treatment is limited to the fight against the symptoms. Despite the specific pathogenesis of each disease, AH is a convenient model for the analysis of common causes underlying these diseases. It is known that the concepts of neurohumoral control of cardiovascular system mainly describe hemodynamics without an integration of additional mechanisms optimizing cellular metabolism. On the other hand, the modem concepts of integrative physiology (IP) are based only on systemic functioning of organs. Meanwhile, a large amount of data ensures that there exist specific metabolites of a mystery functional role on the scale of the body. In our view, it is time for IP's new concepts able to both cover the full range of facts and show the term for breaking the deadlock problems of AH. The purpose of the article is to determine both the actual conceptual problems of theoretical/applied IP, and ways for radical treatment of AH. The research methodology of IP and traditional concepts of AH are subjects of the analysis. It is argued that the focus of research should be focused on physiological supersystems (PSS), integrating mechanisms of cellular physiology with mechanisms of organs systems. The organizational complexity of every PSS is the main problem of its experimental identification, thus computer simulations are proposed for enhancing empirical methods. The problems arising when the researcher will use this combination, are illustrated by the analysis of an energy PSS. It exists in the form of a battery of mechanisms with individual power and speed values, supporting the ATP synthesis in mitochondria. It is shown that even this partial PSS does display situational responses to various scenarios of ATP deficiency in the body. Thus, to overcome the current challenges of IP, researchers need to create the concept of multilevel PSS and develop adequate methods of their evaluation. Perhaps the partial PSS, activated against the lack of ATP in the cells, will become a platform for developing common methodology for exploration of the general class of multilevel PSS.