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The renin-angiotensin system (RAS) is a pivotal system for regulating blood volume, electrolyte balance, and systemic vascular resistance. The system exerts its functions through various central targets, particularly those located in the brain. Among these, the subfornical organ (SFO) plays a unique and integrative role. High permeability and the lack of a functional blood-brain barrier (BBB) enable the organ to monitor changes in body fluid composition and transduce these signals into autonomic and behavioral outputs. Its extensive neural projections facilitate the monitoring of circulating factors. The interaction between the RAS and the SFO has gained great attention regarding the activation of different receptors, including angiotensin AT1 and AT2 receptors, and molecular pathways such as protein kinase C, mitogen-activated protein kinase, and growth factor receptor pathways. These interactions are involved in disorders including hypertension and chronic kidney disease. This review summarizes current evidence on RAS-SFO interactions and their pathological significance.