Inositol-(1,4,5)-triphosphate receptors (InsP3Rs) are ligand-gated Ca2+ channels that control Ca2+ release from intracellular stores and play a central role in a wide range of cellular responses. In most epithelial cells, InsP3Rs are not uniformly distributed within the endoplasmic reticulum (ER) membrane with the consequence that agonist stimulation results in compartmentalized Ca2+ signals. Despite these observations, little is known about the mechanisms that regulate the intracellular localization of InsP3Rs. Here, we report that exogenously expressed InsP3R1-GFP and endogenous InsP3R3 interact with the K-Ras-induced actin-binding protein (KRAP) in both differentiated and undifferentiated Madin-Darby canine kidney (MDCK) cells. KRAP mediates InsP3R clustering in confluent MDCK cells and functions as an adapter, linking InsP3Rs to vimentin intermediate filaments (IF). Upon epithelial differentiation, KRAP and vimentin are both required for InsP3R accumulation at the periphery of MDCK cells. Finally, KRAP associates with vimentin in chicken B lymphocytes and with keratins in a breast cancer cell line devoid of vimentin. Collectively, our data suggest that IF in conjunction with KRAP may govern the localization of InsP3Rs in a large number of cell types (including epithelial cells) and in various physiological or pathological contexts.