This Notice of Funding Opportunity (NOFO) invites applications to propose human studies to better understand the factors underlying the response variability to exercise training in older adults. This NOFO encourages studies to identify systemic modulators, biomarkers, and other potential mechanisms underlying exercise variation in endpoints that are clinically relevant for older adults. This NOFO also encourages trans-disciplinary studies utilizing innovative design methods and analytical approaches combined with clinical phenotyping to disentangle the complicated relationships between endogenous and exogenous factors that drive response variation to exercise. Elucidating factors and mechanisms that underlie variations in exercise response and the extent to which these factors are modifiable may enable more precise and efficacious exercise prescriptions to optimize the clinical efficacy of exercise training in older adults.