The IGF-1 receptor is expressed in many cell types, and its activation by its ligands is a required step for the proliferation of many cells in vivo and in vitro. In most cells in culture, requiring more than one growth factor for growth, the IGF-1 receptor can be found in one of two different modes: in the first mode, although it is autophosphorylated by its ligands and induces the expression of specific genes, it does not transmit a mitogenic signal. In the alternative mode, i.e., after priming with an unrelated growth factor, the IGF-1 receptor responds to its ligands with a mitogenic stimulus. This review examines briefly the possible alternatives to explain this different behavior, which is crucial to our understanding of the control of cellular proliferation.