Abstract: Melanoma is one of the most aggressive cutaneous malignancies with an increasing incidence in recent decades, especially in western countries. It is considered to be an incurable disease, and patients with metastatic melanoma survive no more than 5 years. Despite rapid improvement in chemotherapy and immunotherapy, such as anti-PD-1/PD-L1 treatment, the high frequency of drug resistance remains a difficult problem. Thus, recent research has shifted slightly to the field of biomarkers to achieve the more urgent goal of aiding in the diagnosis and predicting response and resistance to therapy. With the development of fascinating technologies in laboratory testing, numerous novel biomarkers have been identified, and some of them exhibit potential as therapeutic targets. In this review, we summarize the latest genetic and epigenetic biomarkers, discuss their role in the prediction of disease progression and response to therapies, and provide insights into potential targets for future therapies.