The goals of the present work are to evaluate the sensitizing/protective effect of melanin in the cytotoxicity and genotoxicity of ionizing radiation, including induced oxidative stress modulation in malignant melanoma cells in presence and absence of melanin, and to interpret obtained results in the perspective of melanoma or other malignancies radiotherapy. The biological effects of ionizing radiation interaction are explored with special focus on the biologic effects of radiation in normal and melanoma cells and the interaction of melanin with the damage caused by ionizing radiation (IR). Melanin is a class of pigments present in almost all living beings. Melanin protection against UV radiation is widely acknowledged, but not completely understood; some recent studies claim that melanin can also play an in important role in protection against ionizing radiation. However, other studies evidenced that melanogenesis may be a source of reactive substances, some of them carcinogenic. This study is an attempt to clarify which behavior prevails in IR-exposed cells.