It has been the general opinion that the IGF-IR and its ligands (IGF-I and IGF-II) are mediators of mitogenic effects, whereas insulin and its receptor (IR) are mediators of metabolic effects. However, the actions and interactions of these two systems are complex. Moreover, in recent years, several lines of evidence indicate that components of the IGF system are involved in cancer pathogenesis along with the insulin and the IR. The role of insulin and its receptor in tumorigenesis is supported by several epidemiological studies indicating that diseases characterized by hyperinsulinemia (type 2 diabetes and obesity) are associated with an increased risk for cancer . Furthermore, recent studies have partially elucidated the molecular basis of IR involvement in cancer. These studies include the aberrant expression of the IR in malignant cells, in particular IR isoform A (IR-A), which is a second receptor for IGF-II, and the formation of IR/IGF-IR hybrids. These new receptors expand the pool of functional binding sites for IGF-I and IGF-II and trigger various biological effects. Moreover, atypical IRs and IGF-IRs may also be expressed in cancer cells, thus further increasing the complexity of these systems. This “IGF network” is also complicated by its cross-talk with other molecular systems, such as oncogenes/antioncogenes, other growth factor receptors, and sex steroid hormones. In this chapter, we will focus on the role of IGF-IR and IR systems and their cognate ligands in tumorigenesis. These systems have important implications for both the prevention and the treatment of common human malignancies that are characterized by dysregulation of the IGF system.