Aggressive cancer cells manifest stem-cell-like qualities that allow them to self-renew and to derive a heterogeneous tumor. Ultimately, this multipotent phenotype facilitates metastasis and resistance to therapy. Cancer cells likely acquire and maintain multipotent phenotypes by aberrantly expressing embryonic factors, such as Nodal and Notch, which maintain pluripotency in normal embryonic stem cell types. Recent studies have shown that Nodal, an embryonic morphogen belonging to the transforming growth factor-beta (TGF-β) superfamily, is aberrantly expressed in melanoma and breast carcinoma cells. Moreover, Nodal facilitates breast cancer and melanoma tumorigenesis. During development, Nodal is regulated by the spatial and temporal expression of inhibitors such as Lefty. In aggressive cancer cells, this balance of regulatory mediators is disrupted, leading to unchecked Nodal expression. By exposing aggressive cancer cells to embryonic microenvironments, inclusive of Lefty, Nodal expression is decreased and tumorigenesis is suppressed. Embryonic stem cell-derived factors, such as Lefty, may provide therapeutic modalities that may be used to specifically differentiate and eradicate aggressive cancers.