Growth factor pathways are fundamental in normal tissue regulation and development. In many tissues, factors that function in normal growth and development also have important regulatory roles in transformed malignant cells. The insulin-like growth factor (IGF) system is implicated in the regulation of the malignant phenotype by its effects on proliferation, differentiation, and apoptosis. IGF-I has also been linked to malignant transformation. The role of the IGF-I in cancer has been recognized in both experimental and clinical settings, suggesting that the enhancement of growth factor pathways potentially could increase the risk for cancer development. In this paper, the role of IGF-I signaling in tumor regulation, and the impact of IGF-I modulation using growth hormone replacement therapy are discussed.