One of the recent, significant advances in cancer immunotherapy is the identification of molecules as targets which regulate cell growth by induction of proliferation and survival signalling pathways. Among them, epidermal growth factor receptor and Her2 have been effectively targeted by monoclonal antibodies. Currently, the treatment of cancer has limitations and most cancer deaths result from the local invasion and distant metastasis of tumour cells. An important insight for the understanding of tumour invasion and metastasis came from 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. The human Cripto, a member of the epidermal growth factor-Cripto, Frl1, and Cryptic (EGF-CFC) protein family and a signalling protein during early embryonic development, plays an important role in cancers. Cripto is attached to the cell membrane through a glycosyl-phosphatidylinositol motif, and is upregulated in a wide range of epithelial cancers. In this paper the authors review the role of Cripto expression in tumourigenesis and in EMT to promote tumour invasion, with emphasis that the unique EGF-like region of Cripto plays a critical role in Cripto signalling-mediated tumour growth and EMT. Therefore, the region should be regarded as a therapeutic point for interruption of the oncogenic and metastatic potential of Cripto for cancer immunotherapy.