Currently, skin cancer is one of the most frequent type of cancers. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Melanomas represent 3% of all skin cancers but 65% of skin cancer deaths. Detailed knowledge of melanoma at the molecular level allows the development of new treatment alternatives and to design effective new drugs. There are two approaches in therapy of melanoma in the present is based on immunotherapy and targeted therapy or their combination. Immunotherapy includes immune checkpoint blockades whereas targeted therapy is represented by protein kinase inhibitors. Detailed knowledge of protein structure and the understanding of their role in key signalling pathways in melanoma development lead to the designation of new protein kinase inhibitors in targeted therapy. In the future, it is necessary to conduct further clinical trials and collect more data about overall survival, response rates, appropriate timing and sequence of combination therapy to manage the complexity of melanoma treatment.