The complexity of the IGF-signaling system is further compounded by the ability of IGF-2 to stimulate IRA and IRA/IRB, the ability of both IGF-1 and IGF-2 to stimulate IGF-1R, IGF-1R/IRA, and IGF-1R/IRB, and the crosstalk between IGF-1R and EGFR [13]–[15], all of which appear to constitute pathways for certain cancer cells to escape IGF-1R-targeted therapies, and provide the rational for cotargeting IGF-1R with IR [16], [17] or EGFR/HER2 [18], [19] to enhance treatment efficacy. This evidence concerns the gene INSR and cancer.