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From synthesis to degradation, membrane proteins navigate interwoven networks that control their localization and activity within the cell. At branch points within these networks, protein–protein interactions often determine the flux of individual proteins through specific pathways and thus offer targets for therapeutic modulation. The PDZ (PSD-95, Dlg, and ZO-1) proteins constitute a major family of trafficking regulators. Characterized by the presence of eponymous protein–protein interaction domains (PPIDs), PDZ proteins generally bind the C termini of their partners and help direct their movements throughout the cell. The targets of PDZ regulation include the cystic fibrosis transmembrane conductance regulator (CFTR), the chloride channel mutated in patients with cystic fibrosis (CF).[1] CF is the most common life-threatening autosomal recessive disease among people of European ancestry. In airway epithelia, loss …