Growth of an organism is determined by many factors, including the hormonal milieu. Among the hormones, growth hormone releasing hormone (GHRH), produced by the brain, and growth hormone (GH), secreted from the pituitary, are the most widely studied major regulators of growth in vertebrates. GHRH is the most important brain-derived positive regulator of GH secretion from the pituitary. While its primary and earliest identified role is its stimulatory action on pituitary somatotrophs, emerging research has identified several other effects on tissues including nervous, respiratory, cardiovascular and gonadal tissues, and in regulating metabolic, aging and sleep. Thus, in addition to the stimulation of growth processes mediated by GH, GHRH has direct or indirect regulatory effects on various other cells. These actions are mediated by a G-protein-coupled receptor (GPCR) named GHRH-R and associated cell signaling pathways. GHRH-R is widely presented in the above-mentioned target tissues where GHRH acts. The overarching goal of this chapter is to provide a state-of-the-art comparative review of GHRH biology in vertebrates. Tissue-specific localization, and pituitary and extra-pituitary functions, and mechanism of action of GHRH and GHRH-R are discussed in-depth, while clinical aspects of GHRH are not included. Evolutionary perspectives of GHRH and GHRH-R form and function are also included.