Metastatic melanoma is one of the most resistant tumors to standard chemotherapy approaches. The median overall survival of patients diagnosed with metastatic melanoma is lower than 9 months. Current approved treatments offer only marginal survival advantages. New immunotherapeutic targets have appeared recently trying to modulate the host immune response against the tumor. New targeted agents have changed the standard of care of other solid tumor types like breast cancer. Here, we discuss the new advances and achievements in the treatment of this highly resistant disease.