Despite advances in drug discovery programs and molecular approaches for identifying drug targets, incidence and mortality rates due to melanoma continue to rise at an alarming rate. Existing preventive strategies generally involve mole screening followed by surgical removal of the benign nevi and abnormal moles. However, due to lack of effective programs for screening and disease recurrence after surgical resection, there is a need for better chemopreventive agents. Although sunscreens have been used extensively for protecting from UV-induced melanomas, results of correlative population-based studies are controversial, with certain studies suggest increased skin cancer risk in sunscreen users. Therefore, these studies require further authentication to conclusively confirm the chemoprotective efficacy of sunscreens. This chapter reviews the current understanding regarding melanoma chemoprevention and the various strategies used to accomplish this objective.