Most health research to date has been pursued within the confines of scientific disciplines that are guided by their own targeted questions and research strategies. Although useful, such inquiries are inherently limited in advancing understanding the interplay of wide-ranging factors that shape human health. The Oxford Handbook of Integrative Health Science embraces an integrative approach that seeks to put together sociodemographic factors (age, gender, race, socioeconomic status) known to contour rates of morbidity and mortality with psychosocial factors (emotion, cognition, personality, well-being, social connections), behavioral factors (health practices) and stress exposures (caregiving responsibilities, divorce, discrimination) also known to influence health. A further overarching theme is to explicate the biological pathways through which these various effects occur. The biopsychosocial leitmotif that inspires this approach demands new kinds of studies wherein wide-ranging assessments across different domains are assembled on large population samples. The MIDUS (Midlife in the U.S.) national longitudinal study exemplifies such an integrative study, and all findings presented in this collection draw on MIDUS. The way the study evolved, via collaboration of scientists working across disciplinary lines, and its enthusiastic reception from the scientific community are all part of the larger story told. Embedded within such tales are important advances in the identification of key protective or vulnerability factors: these pave the way for practice and policy initiatives seeking to improve the nation’s health.