Kir2 channels are expressed in a variety of tissues including heart, brain and vascular smooth muscle cells. Kir2 channels are regulated by a variety of second messenger pathways including PKA, PKC and phosphatidylinositol-bisphosphate (PIP2). Kir2 channels are clustered with modulator proteins at the plasma membrane and are linked to the cytoskeleton by scaffolding adaptor proteins to allow regulation of their trafficking. Consequently, Kir2 channel trafficking is regulated by a variety of proteins including Rho, AKAP79, SAP97, Chapsyn 110, filamin-A, PSD95, CASK, Veli, and Mint1. Several classical adaptor proteins contain SH2 and SH3 domains. The Grb-protein family contains a SH2 domain which is flanked on both sides by a SH3 domain. Here, we analyse the functional effects of Grb- proteins on Kir2 channels. We find that Kir2.3 and Kir2.4 but not Kir2.1 and Kir2.2 channels are functionally down regulated upon coexpression with specific Grbs. The selective activity of Grbs is also indicated by the lack of down-regulation of Kir2.3/4 by one Grb- protein.