The protumorigenic insulin‐like growth factor (IGF)‐II is highly expressed in a significant fraction of human hepatocellular carcinomas (HCC). However, a functional dissection that clarifies the contribution of IGF‐II–binding receptors in tumor progression and a respective molecular characterization of IGF‐II signaling has not been performed. Therefore, expression of IGF‐II and its receptors IGF‐receptor type I (IGF‐IR) and insulin receptor (IR) was efficiently blocked using small interfering RNA (siRNA) in HCC cells. Despite functional IR‐signaling, oncogenic IGF‐II effects such as tumor cell viability, proliferation, and anti‐apoptosis were solely transmitted by IGF‐IR. Although IGF‐II signaling was previously not described in the context of HCC cell migration, the IGF‐II–dependent expression profile displayed a high percentage of genes involved in cell motility and adhesion. Indeed, IGF‐II overexpression promoted HCC cell migration, especially in synergy with hepatocyte growth factor (HGF). The therapeutic relevance of IGF‐II/IGF‐IR signaling was tested in vitro and in a murine xenograft transplantation model using the IGF‐IR inhibitor picropodophyllin (PPP). IGF‐IR inhibition by small molecule treatment efficiently reduced IGF‐II–dependent signaling and all protumorigenic properties of the IGF‐II/IGF‐IR pathway. Conclusion: In human HCC cells, IGF‐IR but not IR is involved in oncogenic IGF‐II signaling. Autocrine stimulation of IGF‐II induces HCC motility by integration of paracrine signals for full malignant competence. Thus, activation of IGF‐II/IGF‐IR signaling is likely a progression switch selected by function that promotes tumor cell dissemination and aggressive tumor behavior. (HEPATOLOGY 2008.)