Background: Variations in genotype may contribute to heterogeneity in functional adaptations to exercise. Methods: A systematic search of eight databases was conducted, and 9,696 citations were screened. Results: Eight citations from seven studies measuring 10 single-nucleotide polymorphisms and nine different functional performance test outcomes were included in the review. There was one observational study of physical activity and six experimental studies of aerobic or resistance training. The ACE (D) allele, ACTN3 (RR) genotype, UCP2 (GG) genotype, IL-6-174 (GG) genotype, TNF-α-308 (GG) genotype, and IL-10-1082 (GG) genotype all predicted significantly superior adaptations in at least one functional outcome in older men and women after prescribed exercise or in those with higher levels of physical activity. Conclusion: There is a small amount of evidence that older adults may have better functional outcomes after exercise/physical activity if they have specific alleles related to musculoskeletal function or inflammation. However, more robust trials are needed.