Clinical and experimental evidence obtained over the last three decades has collectively identified the insulin-like growth factor (IGF) axis as a major player in human cancer progression. This has led to a concerted effort to target the IGF axis, particularly the IGF-I receptor, for cancer therapy and has already resulted in the development of several inhibitors including insulin-like growth factor-I receptor (IGF-IR) antibodies and specific kinase inhibitors that have advanced into the clinic, with promising results. Detailed reviews on the role of the IGF-IR in malignancy based on animal studies and clinical evidence and on current therapeutic strategies for targeting the IGF axis are provided by other chapters in this collection. In this chapter, we review the epidemiological studies that have contributed to the identification of circulating IGF levels as a potential cancer risk factor and discuss possible reasons for, and the implications of, the disparity in the results obtained in different clinical studies. In addition, recent evidence, based on gene and protein arrays, that identifies IGF axis proteins as potential molecular regulators of tumor invasion is also reviewed highlighting the potential functional relevance of circulating and tumor-derived IGFs to cancer progression and metastasis.