The role of, perhaps, the least understood biogenic amine, serotonin, goes beyond transmitting information within the neuroendocrine system. Serotonin has emerged as a critical factor in diverse signaling events across various organs and tissues. In the central nervous system, serotonin, also referred to by its chemical name 5-hydroxytryptamine, regulates behavior, mood, anxiety, sleep, and learning. In the periphery, serotonin signaling is a critical factor in gastrointestinal homeostasis, platelet activation, mammary gland development, lactation, and involution. Various aspects of mammary and gut physiology depend on related functions, where mechanical and biochemical signals converge. In this chapter, we explore some of the overlapping mechanosensory functions modulated by serotonergic signaling that characterize the relatively static mammary gland and the mechanical active gastrointestinal system in their physiologic and disease states.