Melanoma derived from melanocytes is the most aggressive genre of skin cancer. Although the considerable advancement in the study of human cancer biology and drug discovery, most advanced melanoma patients are inevitably unable to be cured. With the emergence of nanotechnology, the use of nano-carriers is widely expected to alter the landscape of melanoma treatment. In this review, we will discuss melanoma biology, current treatment options, mechanisms behind drug resistance, and nano-based solutions for effective anti-cancer therapy, followed by challenges and perspectives in both pre-clinical and clinical settings.