It has become increasingly evident that bidirectional ("top-down and bottom-up") interactions between the brain and peripheral tissues, including the cardiovascular and immune systems, contribute to both mental and physical health. Therapies directed toward addressing functional links between mind/brain and body may be particularly effective in treating the range of symptoms associated with many chronic diseases. In this paper, we describe the basic components of an integrative psychophysiological framework for research aimed at elucidating the underlying substrates of mind-body therapies. This framework recognizes the multiple levels of the neuraxis at which mind-body interactions occur. We emphasize the role of specific fronto-temporal cortical regions in the representation and control of adverse symptoms, which interact reciprocally with subcortical structures involved in bodily homeostasis and responses to stress. Bidirectional autonomic and neuroendocrine pathways transmit information between the central nervous system and the periphery and facilitate the expression of affective, autonomic, hormonal, and immune responses. We propose that heart rate variability (HRV) and markers of inflammation are important currently available indices of central-peripheral integration and homeostasis within this homeostatic network. Finally, we review current neuroimaging and psychophysiological research from diverse areas of mind-body medicine that supports the framework as a basis for future research on the specific biobehavioral mechanisms of mind-body therapies.