Signals from the IGF-IR and other members of the IR family contribute to the growth, survival, adhesion, and motility of tumor cells. These signals are initiated through recruitment of adapter proteins including the IRS family and Shc proteins, and are mediated through the PI3-kinase, mitogen activated protein (MAP) kinase and stress-activated protein kinase (SAPK) pathways. Regulation of signaling responses from the IGF-IR involves the actions of regulatory adapter proteins including RACK1 and Grb10 that recruit or sequester cytoplasmic proteins, and the actions of phosphatases including tyrosine PTP-1B, PTEN, and PP2A. This review focuses on the signaling pathways that are activated by the IGF-IR in tumor cells, the mechanisms of regulation of these pathways by adapter proteins and phosphatases, and how modulation of IGF-IR signaling could contribute to cancer progression.