Stimulation of dopamine receptors in the lung or kidney epithelia has distinct and opposite effects on the function of Na,K-ATPase, which results in increased Na⁺ absorption across the alveolar epithelium and increased sodium excretion via the kidney epithelium. In the lung, dopamine increases Na,K-ATPase by increasing cell basolateral surface expression of Na⁺,K⁺-ATPase molecules, whereas in the kidney epithelia it decreases Na⁺,K⁺-ATPase activity by removing active units from the plasma membrane by endocytosis. The opposite effects of dopamine over the same target (the Na⁺,K⁺-ATPase) involve the activation of a distinct signaling network that it is target specific, and has a different spatial resolution. Understanding the specific signaling pathways involved in these actions of dopamine and their hierarchical organization may facilitate the drug discovery process that could lead to the design of new therapeutic approaches to clear lung edema in patients with acute lung injury and to decrease fluid overload during congestive heart failure and hypertension.