Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share significant homology, distinct functions have been attributed to each family member in both normal and tumor cells. In cancer, IRS-2 is positively associated with aggressive tumor behavior. In the current study, we show that IRS-2 expression, but not IRS-1 expression, is positively regulated by hypoxia, which selects for tumor cells with increased metastatic potential. We identify IRS-2 as a novel hypoxia-responsive gene and establish that IRS-2 gene transcription increases in a hypoxia-inducible factor-dependent manner in hypoxic environments. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. Functionally, the elevated expression of IRS-2 facilitates breast carcinoma cell survival and invasion in hypoxia. Collectively, our results reveal a novel mechanism by which IRS-2 contributes to the aggressive behavior of hypoxic tumor cells.