Clear links between cancer and cellular signaling triggered by the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) and its cognate ligands (IGF-I and IGF-II) have been reported throughout the past two decades. Experimental results suggest that the pharmaceutical targeting of this signaling pathway could be beneficial for the treatment of cancer. Here, more recent advances towards potentially clinically viable strategies to interfere with the function of IGF-IR will be discussed.