Growth hormone (GH) plays a pivotal role in many physiological processes in humans, and in other mammalian and non-mammalian vertebrate species, through actions on somatic growth, tissue development and repair, and intermediary metabolism. This review will focus on mechanisms of GH actions on gene expression, primarily from the perspective of the genes that encode proteins stimulated by GH to regulate somatic growth, especially insulin-like growth factor 1 (IGF-I), but also others that are induced or repressed by GH. Topics to be discussed will include a brief overview of GH-mediated signal transduction pathways and how these cascades alter the functions of responsive transcription factors, with a specific focus on STAT5B, a key member of the signal transducers and activators of transcription family, characterization of essential GH-regulated genes, and elucidation of mechanisms of their regulation from biochemical, genetic, and genomic perspectives.