Cripto-1 is an oncogenic protein that belongs to the epidermal growth factor (EGF)-cripto-1/FRL1/cryptic (CFC) family. It has been shown to stimulate tumorigenesis and metastasis by promoting cancer cell proliferation, epithelial-to-mesenchymal transition (EMT), and tumor angiogenesis. However, the role of Cripto-1 in cell survival and apoptosis remains largely undefined. In the present study, we found that Cripto-1 is significantly upregulated in a number of human cancer cell lines. The membrane-associated but not the soluble form of Cripto-1 promotes resistance to drug-induced caspase-3 cleavage, an indicator of apoptosis. Consequently, Cripto-1 silencing sensitizes human cancer cells to chemotherapy drugs including cytarabine, cisplatin and taxol. Our mechanistic studies revealed that Cripto-1 promotes apoptosis resistance by inducing NF-κB-mediated Survivin expression through activation of TAK-1. We also found that Cripto-1 silencing does not affect growth of un-treated cancer cells, and Cripto-1 forms self-assembled punctiforms and changes its subcellular distribution upon cytarabine treatment. Thus, the anti-apoptotic activity of Cripto-1 could be an inducible function that can be activated by external stimuli such as drug stimulation. Our findings suggested that targeting the Cripto-1/TAK-1/NF-κB/Survivin pathway may be an effective approach to combat apoptosis resistance in cancer.