The polarized location and cell surface density of different inwardly rectifying (Kir) channels is precisely controlled in the renal collecting duct for potassium balance. We have previously shown that Kir 1.1 (ROMK, KCNJ1) (1) and Kir 2.3 (2,3) channels interact with separate PDZ proteins to differently control polarized trafficking. Here we discuss our recent observations that a hierarchical trafficking program controls cell surface expression of the ROMK channel, involving PDZ-protein interaction and phosphorylation-dependent release from the endoplasmic reticulum. Protein-protein interaction studies indicate that NHERF-2, a PDZ protein, has the capacity to organize a multimeric protein complex, involving the ROMK channel, PKA, and the aldosterone-induced kinase, SGK-1 (4). As determined by in vivo and in vitro phosphorylation assays, serine 44 in ROMK1 is a substrate for PKA and SGK-1 phosphorylation. Phosphorylation of this residue absolutely required to drive traffic of newly synthesized channels to the plasma membrane. ROMK channels were found to acquire mature glycosylation in a serine 44-phosphorylation dependent manner, consistent with a phosphorylation-dependent trafficking step within the endoplasmic reticulum/Golgi. Serine 44 neighbours a string of three “RXR” motifs, reminiscent of basic trafficking signals involved in directing early transport steps within the secretory pathway. Mutational analysis revealed that the neighboring arginine residues are necessary for cell surface expression, identifying a structure that determines export in the biosynthetic pathway. Suppressor mutations in a putative dibasic ER retention signal, located within the cytoplasmic C-terminus (K370A, R371A), restored cell surface expression and activity of the phospho-null S44A channel to levels exhibited by the phospho-mimic S44D channel (5). In summary, we have found that phosphorylation of S44 drives an early export step within the secretory pathway by overriding an independent endoplasmic reticulum localization signal. Thus, a balance of intracellular retention and phosphorylation-dependent export controls Kir1.1 cell surface density. Phosphorylation of S44 by SGK-1 provides a mechanism to explain the requirement of aldosterone for maximal up regulation of the secretory channel observed upon dietary potassium loading. Phosphorylation by PKA offers an explanation for vasopressin-dependent regulation of potassium channel density. Efforts to elucidate the structural basis for the phosphorylation-dependent trafficking signal will be discussed.