Whereas there are many varied roles of insulin-like growth factor I (IGF-I), and it exists in different biocompartments, there is abundant scientific evidence demonstrating that IGF-I is an important metabolic biomarker associated with a variety of health- and exercise-related outcomes. In most cases (muscle, bone, tendon, body composition, and cognitive function), elevated IGF-I concentrations are considered beneficial; however, cancer remains a notable exception. Although the fact that both increased and decreased IGF-I concentrations can be considered as reflective of favorable and beneficial health outcomes and may seem as a paradox and even contradictory, it is important to emphasize that, in both cases, measured IGF-I concentrations do offer important insight into physiological processes. The precise and relative role of systemic versus locally produced IGF-I in mediating the outcomes of physical activity is still not clearly delineated, but it does seem as though local IGF-I is consistently upregulated with both acute and chronic exercises; whereas in certain situations, circulating IGF-I may actually decrease. Although perhaps counterintuitive to the known anabolic role that IGF-I exerts, positive neuromuscular training adaptations can occur in the presence of decreases or no changes in circulating IGF-I. These observations, however, should not be interpreted to conclude that the role of circulating IGF-I lacks importance or relevance in contributing to enhanced musculoskeletal health as evidenced by the liver IGF-I-deficient mouse model. Because of the ubiquitous nature of IGF-I, prospective experimental approaches involving physical activity that can sample and measure IGF-I in the body's various biocompartments (i.e., blood, interstitial fluid, muscle) with the most biologically relevant assays are encouraged. We believe that such endeavors will provide greater understanding in the complex role that IGF-I possesses in mediating exercise-induced adaptations.