Our understanding of oncogenetics and of the molecular mechanisms involved in melanoma development and signaling has dramatically changed in recent years. Today, melanomas are also classified based on molecular alterations. Emerging molecular therapies are targeted against specific mutations in melanoma. An example of targeted therapies is the successful treatment of KIT-mutant melanoma with the kinase inhibitor imatinib. Highly selective BRAF-inhibitors are likewise under clinical development and show encouraging clinical responses. An increasing number of targeted drugs will emerge in the coming years, based on molecular diagnostics and classification. The present article reviews signaling pathways in melanocytes and alterations in melanoma that are a prerequisite to understanding modern cancer therapies in melanoma.