Regular physical activity and exercise training induce several beneficial changes in physiological and biological pathways that lead to better physical performance and improved health outcomes. However, it is evident that there are marked inter-individual differences in physiological changes brought about by regular physical activity. The concept of heterogeneity in responsiveness to standardized exercise programs was first introduced over 25 years ago. The most extensive data on the individual differences in trainability come from the HERITAGE Family Study, where 742 healthy but sedentary subjects followed a highly standardized, well-controlled, laboratory-based endurance-training program for 20 weeks. For example, the average increase in maximal oxygen consumption was 384 (SD 202) mL, but the training responses varied from no change to increases of more than 1 000 mL O₂ per minute. A similar picture emerged for training-induced changes in several other phenotypes, such as blood pressure, heart rate, stroke volume, plasma insulin and lipid levels, and skeletal muscle traits. This high degree of heterogeneity in responsiveness to a fully standardized exercise program was not accounted for by age, gender, or ethnic differences. However, the high and low responses to regular exercise exhibited significant familial aggregation, i.e., there were families with mainly low responders and others in which all family members show significant improvements. The maximal heritability estimates for training response phenotypes have ranged from 20 % to 60 %. These observations support the notion that individual variability is a normal biological phenomenon, which may largely reflect genetic diversity. Understanding the mechanisms that contribute to the variability in responsiveness to exercise training will ultimately allow us to use physical activity more efficiently in primary and secondary prevention of chronic diseases.