Clathrin-mediated endocytosis dynamically regulates cell membrane abundance of CFTR and plays an essential role in CFTR-dependent Cl^- conductance in fluid-transporting epithelia. It requires two closely related, but distinct processes: assembly of the clathrin coat and recruitment of cargo proteins for endocytosis. The assembly polypeptide-2 complex (AP-2) is the prototypical endocytic adaptor responsible for optimal clathrin coat formation. Disabled-2 (Dab2) is a clathrin associated sorting protein (CLASP) that also mediates clathrin assembly and cargo selection. Both of these complexes have clearly been shown to play roles in CFTR endocytosis in cells that endogenously express the channel. However, their precise functions exhibit cell-specific differences. While Dab2 appears to play a central role in CFTR recruitment to the clathrin coat in airway epithelial cells, it does not play a direct role in CFTR endocytosis in intestinal epithelial cells. Here, we review our current understanding of the role of Dab2 in CFTR endocytosis in different tissues. Next, we present new data demonstrating the role of Dab2 in endocytosis of the most commonly mutated CFTR gene product, ∆F508-CFTR, in human airwy epithelial cells. Finally we discuss the potential therapeutic implications of targeting the functional interaction between ∆F508-CFTR and Dab2.