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A summary of the evidence for a contribution of genetic variability to physical activity–related traits is presented. The availability of a reference human DNA sequence has made it possible to screen individuals and populations for the presence of genomic differences. Even though more than 100 million DNA variants have been identified, human beings share a genomic sequence, which is more than 99% identical. Four major lessons can be derived from ongoing genomic and genetic studies. First, the connection between a genotype and a phenotype is highly complex. Second, the expression of genes is regulated via multiple interacting mechanisms. Third, redundancy and compensatory mechanisms are ubiquitous. Fourth, complex, multifactorial traits are influenced by polygenic systems defined by hundreds and thousands of loci with most alleles characterized by very small effect sizes. The contribution of genetic variability is briefly summarized for human longevity, common chronic diseases, physical activity level, cardiorespiratory fitness in the sedentary state, and in response to exercise programs.