A growing body of evidence indicates that genotype-by-physical activity interactions on various health-related outcomes do exist. Observational studies have shown that relationships between DNA sequence variants and risk factors are significantly different between sedentary and physically active individuals, while exercise intervention studies have demonstrated that genetic variation contributes significantly to interindividual variation in responsiveness to exercise training. The knowledge base on gene-activity interactions will grow considerably within a few years when large observational genome-wide association study (GWAS) consortia will report their findings. Progress with exercise intervention studies will be slower because of resource requirements. However, such studies are desperately needed to fully understand the genetics as well as the exercise biology of complex traits and to confirm the gene-exercise interactions derived from observational studies. Furthermore, development of personalized exercise medicine applications will be difficult or even impossible without a proper understanding of gene-exercise interactions.