Byline: MARK A. SARZYNSKI, Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC; TREVA K. RICE, Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO; JEAN-PIERRE DESPRÈëS; LOUIS PÈëRUSSE; ANGELO TREMBLAY; PHILIP R. STANFORTH, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX; ANDRÈë TCHERNOF; JACOB L. BARBER, Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC; FRANCESCO FALCIANI, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UNITED KINGDOM; CLARY CLISH, Metabolomics Platform, Broad Institute and Harvard Medical School, Boston, MA; JEREMY M. ROBBINS; SUJOY GHOSH; ROBERT E. GERSZTEN; ARTHUR S. LEON, School of Kinesiology, University of Minnesota, Minneapolis, MN; JAMES S. SKINNER, Department of Kinesiology, Indiana University, Bloomington, IN; D. C. RAO, Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO; CLAUDE BOUCHARD, Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA Abstract The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study.