Suppressed insulin/insulin-like growth factor-1 (IGF-1) receptor signaling (“insulin resistance”) in type 2 diabetes leads to impaired wound re-epithelialization. In normal human epidermal keratinocytes (NHEKs), this pathway is primarily activated through the IGF-1 receptor (IGF1R). Despite the critical role of IGF1R in migration and re-epithelialization, the mechanism of its endocytosis and subsequent activation in NHEKs is poorly understood. Flotillin (flot-1), a noncaveolar lipid raft marker, affects receptor tyrosine kinase signaling in cancer cells, but litle is known about its role in normal cells. In starved NHEKs, we found surface IGF1R colocalized with flot-1 using microscopy and coimmunoprecipitation (coIP). Upon IGF-1 stimulation, IGF1R colocalizes both with flot-1 in lipid rafts and with the adaptin complex (αAP1/2) and clathrin in clathrin pits. Interestingly, IGF-1 also promotes colocalization and coIP of flot-1 with clathrin. Despite blockade of endocytosis via clathrin pits with chlorpromazine (CPMZ) or shRNA knockdown of αAP1/2, IGF1R still endocytoses and associates with both flot-1 and clathrin. In addition, flot-1 knockdown or dissociation of flot-1 from IGF1R and clathrin after lipid raft dissolution using methyl-β-cyclodextrin (MβCD) fails to prevent IGF1R internalization with clathrin. In contrast, concurrent shRNA knockdown of flot-1 and αAP1/2 eliminates the association of IGF1R with clathrin and prevents endocytosis and signaling. Similarly, treatment of IGF-1-stimulated NHEKs with both CPMZ and MβCD fully blocks endocytosis and completely abolishes IGF-1-induced phosphorylation of IGF1R, Akt and MEK. These data suggest that IGF1R endocytosis and signaling are controlled by clathrin-dependent endocytosis, mediated by one of two adaptors: flotillin in noncaveolar lipid rafts or the αAP1/2 complex in clathrin pits. The discovery of a flotillin-dependent, clathrin-mediated endocytosis pathway for IGF1R provides a new avenue for drug discovery for diseases with aberrant regulation of IGF1R signaling.