Water and salt metabolism are tightly regulated processes. Maintaining this milieu intérieur within narrow limits is critical for normal physiological processes to take place. Disturbances to this balance can result in disease and even death. Some of the better characterized regulators of water and salt homeostasis include angiotensin II (ANGII), aldosterone, arginine vasopressin (AVP) and oxytocin. Although secretin (SCT) was first described more than hundred years ago, little is known about the role of this classic gastrointestinal hormone in the maintenance of water-salt homeostasis. In recent years, increasing body of evidence suggested that SCT and its receptor play important roles in the central nervous system (CNS) and kidney to ensure that the mammalian extracellular fluid (ECF) osmolarity is kept within healthy range. In this review, we focus on recent advances in our understanding of the molecular, cellular and network mechanisms by which SCT and its receptor mediates the control of osmotic homeostasis. Implications of hormonal cross-talk and receptor-receptor interaction are highlighted.