Apoptosis protease-activating factor-1 (Apaf-1) is a key regulator of the mitochondrial apoptotic pathway, being the central element of the multimeric apoptosome formed by procaspase 9, cytochrome c, and Apaf-1 itself. In this review, the principal aspects about Apaf-1 gene structure and function, and its role in the apoptotic machinery, are described. Moreover, the most recent findings about the involvement of this molecule in melanoma progression and chemoresistance, as well as the clinico-pathological relevance of these findings in the treatment of this deadly disease, are reported.