Abstract While our understanding of pain is rapidly growing, some areas of pain research are lagging behind. This article discusses two current and inter-related gaps in knowledge that are in need of addressing: first, the connections between “brain” and “body” components of pain; and second, the process of endogenous pain resolution. Historical reasons for these research gaps are discussed and solutions are outlined based on an integrative, whole person research approach. These include comprehensive mapping of the mechanosensory and nociceptive innervation of deep tissues; developing objective, non-invasive measurements to quantify the metabolic, structural and mechanical components of the peripheral tissue environment; integrating our understanding of pain pathophysiology, across whole organs and whole body, as well as across bio-psycho-social domains; and understanding the interplay of nervous system and peripheral tissue mechanisms that promote the endogenous resolution of pain and prevent its acute-to-chronic transition. Current NIH-led efforts in these areas are outlined, including several studies within the NIH HEAL (or Help End Addition Long Term) initiative and the National Center for Complementary and Integrative Health's strategic priorities in whole person research.