The development of a new tool, analytic device, or approach frequently facilitates rapid growth in scientific understanding, although the process is seldom linear. The study of heart rate variability (HRV) defined as the extent to which beat-to-beat variation in heart rate varies, is a rapidly maturing paradigm that integrates health and wellness observations across a wide variety of biomedical and psychosocial phenomena and illustrates this nonlinear path of development. The utility of HRV as an analytic and interventive technique goes far beyond its original application as a robust predictor of sudden cardiac death. This Research Topic aims to provide a conceptual framework to use in exploring the utility of HRV as a robust parameter of health status, using a broad and inclusive definition of ‘health’ and ‘well-being’. From the broadest perspective, current biomedical science emerged from shamanistic and religious healing practices and empirically observed interventions made as humans emerged from other hominins. The exponential growth of physics, chemistry and biology provided scientific support for the model emphasizing pathology and disorders. Even before the momentous discovery of germ theory, sanitation and other preventive strategies brought about great declines in mortality and morbidity. The revolution that is currently expanding the biomedical model is an integrative approach that includes the wide variety of non-physio/chemical factors that contribute to health. In the integrative approach, health is understood to be more than the absence of disease and emphasis is placed on optimal overall functioning, within the ecological niche occupied by the organism. This approach also includes not just interventive techniques and procedures, but also those social and cultural structures that provide access to safe and effective caring for sufferers. Beyond the typical drug and surgical interventions - which many identify with the Western biomedical model that currently enjoys an unstable hegemony - such factors also include cognitive-behavioral, social and cultural practices such as have been shown to be major contributors to the prevention and treatment of disease and the promotion of health and optimal functioning. This Integrative Model of Health and Well-being also derives additional conceptual power by recognizing the role played by evolutionary processes in which conserved, adaptive human traits and response tendencies are not congruent with current industrial and postindustrial global environmental demands and characteristics. This mismatch contributes to an increasing incidence of chronic conditions related to lifestyle and health behavior. Such a comprehensive model will make possible a truly personalized approach to health and well-being, including and going far beyond the current emphasis on genomic analysis, which has promised more that it has currently delivered. HRV offers an inexpensive and easily obtained measure of neurovisceral functioning which has been found to relate to the occurrence and severity of numerous physical disease states, as well as many cognitive-behavioral health disorders. This use of the term neurovisceral refers to the relationships between the nervous system and the viscera, providing a more focused and specific conceptual alternative to the now nearly archaic “mind-body” distinction. This awareness has led to the recent and growing use of HRV as a health biomarker or health status measure of neurovisceral functioning. It facilitates studying the complex two way interaction between the central nervous system and other key systems such as the cardiac, gastroenterological, pulmonary and immune systems. The utility of HRV as a broad spectrum health indicator with possible application both clinically and to population health has only begun to be explored. Interventions based on HRV have been demonstrated to be effective evidence-based interventions, with HRV biofeedback treatment for PTSD representing an empirically supported modality for this complex and highly visible affliction. As an integral measure of stress, HRV can be used to objectively assess the functioning of the central, enteric and cardiac nervous systems, all of which are largely mediated by the vagal nervous complex. HRV has also been found to be a measure of central neurobiological concepts such as executive functioning and cognitive load. The relatively simple and inexpensive acquisition of HRV data and its ease of network transmission and analysis make possible a promising digital epidemiology which can facilitate objective population health studies, as well as web based clinical applications. An intriguing example is the use of HRV data obtained at motor vehicle crash sites in decision support regarding life flight evacuations to improve triage to critical care facilities. This Research Topic critically addresses the issues of appropriate scientific and analytic methods to capture the concept of the Integrative Health and Well-being Model. The true nature of this approach can be appreciated only by using both traditional linear quantitative statistics and nonlinear systems dynamics metrics, which tend to be qualitative. The Research Topic also provides support for further development of new and robust methods for evaluating the safety and effectiveness of interventions and practices, going beyond the sometimes tepid and misleading “gold standard” randomized controlled clinical trial.