This chapter reviews the endocrine pathway and mechanism of action of growth hormones and insulin-like growth factor-1 (IGF-1). The chapter explains the effects of growth hormone and/or IGF-1 replacement on the aging phenotype. Growth hormone binds with high affinity to its receptor, found in tissues throughout the body, and activation of this receptor stimulates the synthesis and secretion of IGF-1. This receptor belongs to the cytokine family of receptors and its activation facilitates the association of intracellular components of the receptor with JAK2 into a complex with subsequent phosphorylation of both proteins. The impaired secretion of growth hormone and the subsequent decline in IGF-1 appear to influence the maintenance and viability of multiple organ systems as well as subsequent functional and behavioral outcomes. However, there are often deleterious effects associated with growth hormone replacement therapy in the elderly-including edema, arthralgias, carpal tunnel, muscle pain, and bloating. © 2005 Elsevier Inc. All rights reserved.