From an evolutionary perspective, the neuroendocrine system is a robust, complex, and sophisticated communication mechanism by which organisms coordinate and integrate signals to regulate a wide range of physiological processes, maintain homeostasis, and enable an adaptive response. One of the key events of the evolution of vertebrates was the appearance of the pituitary gland and the formation of the hypothalamus–pituitary system. This chapter discusses the molecular evolution of the structure and function of hormones and receptors, the complexity of the vasculature, as well as changes in the structural characteristics, diversity of composition, and zonal distribution of endocrine cells in the gland. The diversification of hypothalamic–pituitary communication mechanisms in vertebrates is reviewed, ranging from passive diffusion to neuroglandular and neurovascular pathways, such as the hypophyseal portal system. This chapter explores the increasing complexity in the integration of the regulation of the endocrine axes in vertebrates and their degree of independence in operation, with emphasis on the physiological implications and specific adaptations of the dynamics of the axes regulating growth, metabolism, and reproduction. Finally, pulsatile hormone secretion is addressed as an adaptive feature of high-level signaling that involves a system of internal glandular regulation. This results from the interplay between intercellular communication elements, highly plastic cellular networks, and the vascular system.