Metastatic melanoma continues to be a significantly deadly cancer with a cure rate of < 20% and a median survival of 6 - 9 months. The aggressiveness associated with metastatic melanoma is largely attributable to its inherent plasticity, a property that is mediated by the secretion of Nodal, a stem-cell associated protein belonging to the transforming growth factor-beta superfamily. This is supported by the observations that Nodal expression is limited to invasive vertical growth phase and metastatic melanoma lesions, and that inhibition of Nodal signaling promotes the reversion of metastatic melanoma cells toward a more differentiated, less invasive non-tumorigenic phenotype. Hence, due to its restricted expression pattern and function as a melanoma-tumor-promoter, Nodal (and its signaling partners) present unique targets for both immunologic and pharmacologic therapies.