The success of molecular target-based cancer therapy exampled by Herceptin targeting Her2 indicates that cancer immunotherapy involves identifying and targeting key molecular drivers of cancer. Recently, the human Cripto, a founding member of the epidermal growth factor-Cripto-FRL1-Cryptic (EGF-CFC) protein family has been demonstrated to be a unique molecule and could be targeted by anti-Cripto monoclonal antibodies for the treatment of cancer. Cripto plays an important role in embryonic development, tumorigenesis, cancer cell proliferation and survival. Cripto is upregulated in most epithelial cancers but is absent or weakly expressed in normal cells. Cripto expression is associated with tumorigenesis and invasion. Cripto is also involved in tumor metastasis, which is strongly supported by the recent discovery that the phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial mesenchymal transition (EMT) that occurs during embryonic development. In this review, we emphasize that the EGF-like region of Cripto plays a critical role in Cripto signaling-mediated tumor growth and EMT. Therefore the EGF-like region should be regarded as a therapeutic point for monoclonal antibody (MAb) intervention. The mechanisms of action of these MAbs to the EGF-like region of Cripto are most likely through intervention of c-Src signaling. The CFC region of Cripto is another region to be targeted for treatment of cancer, as the Cripto can bind to activin B through the CFC region to stimulate cell proliferation. The MAbs to the CFC region block the binding of Cripto and activin B and result in an inhibition of cell growth. Therefore the MAbs to Cripto may be of value in the treatment of various cancers.