Insulin-like growth factors (IGFs) are key regulators of cell proliferation, differentiation, and transformation, and are thus pivotal in cancer, especially breast, prostate, and colon neoplasm. Their potent mitogenic and anti-apoptotic actions depend primarily on their availability to bind to the signaling IGF cell surface receptors. One mechanism by which IGF-II availability is thought to be modulated is by binding to the nonsignaling IGF-II receptor (IGF2R). This binding is essentially mediated by domain 11 in the multidomain IGF2R extracellular region. The crystal structure of domain 11 of the human IGF-II receptor (IGF2R-d11) has identified a putative IGF-II binding site, and a nuclear magnetic resonance (NMR) solution structure for the IGF-II ligand has also been characterized. These structures have now been used to model in silico the protein-protein interaction between IGF-II and IGF2R-d11 using the program 3D-Dock. Because the IGF-II data comprise an ensemble of 20 structures, all of which satisfy the NMR constraints, the docking procedure was applied to each member of the ensemble. Only those models in which residue Ile1572 of IGF2R-d11, known to be essential for the binding of IGF-II, was at the interface were considered further. These plausible complexes were then critically assessed using an array of analysis techniques including consideration of additional mutagenesis data. One model was strongly supported by these analyses and is discussed here in detail. Furthermore, we demonstrate in vitro experimental support for this model by studying the binding of chimeras of IGF-I and IGF-II to IGF2R fragments.