Induction of insulin-like growth factor-I (IGF-I) expression is thought to be a major contributor to muscle development and to muscle adaptation in response to exercise training (1,2). IGF-I expression increases in skeletal muscle in response to mechanical load or muscle injury. The increase in IGF-I expression is an initiating event for downstream signaling events that are thought to regulate mechanisms including protein synthesis and cellular proliferation (1,2). Much of our understanding concerning the mechanistic roles of IGF-I has been delineated by gain of function experiments where exogenous IGF-I has been delivered to the muscle (3). Unfortunately, loss of function experiments has been prohibitive because traditional knockout models of the IGF-I system are often fatal. To gain a better understanding of IGF-I, my laboratory has utilized a transgenic mouse model that expresses a dominant negative IGF-I receptor specifically in skeletal muscle (MKR) (4). These mice express normal amounts of IGF-I, but due to the mutated IGF-I receptor the muscle does not respond to IGF-I exposure. These mice are viable, but exhibit ~20-40% reductions in skeletal muscle mass, with no differences detected in heart mass. We have used these mice to examine the role of IGF-I in muscle hypertrophy and signaling mechanisms that regulate protein translation. Specifically, we have found using the functional overload model (FO) that the muscle hypertrophic response of the MKR mice is equivalent to that of the WT mice (4). These data suggest that a functional IGF-I receptor is not necessary for muscle hypertrophy. Further, we have found that mutation of the IGF-I receptor does not prevent load-induction of the Akt-mTOR pathway in the FO model (4). These data indicate that when using a chronic model of mechanical loading activation of the IGF-I receptor is not critical for the induction of the Akt-mTOR signaling pathway. IGF-I is also thought to be critical in the recovery from muscle injury. Interestingly, in preliminary studies we have found that the MKR mice are very susceptible to contraction-induced muscle injury compared to WT mice. These data suggest that the IGF-I receptor may provide a protective effect to the muscle. Clearly, much of our understanding of the role of IGF-I continues to be unraveled, but it is clear that the role of IGF-I is complex and will necessitate more studies.