The advent of personalized medicine has ushered in a new era for cancer therapy with a significant impact on the management of advanced melanoma. Molecular targeted therapies have shown promise in the management of various malignancies, including melanoma, with lower toxicity profiles and better overall survival as compared with conventional therapy. The discovery of BRAF mutations in melanoma led to the development of BRAF inhibitors for the treatment of advanced melanoma. However, growing concerns over drug resistance to molecular targeted therapies including BRAF inhibitors, have spurred efforts to elucidate additional molecular targets for the treatment of advanced melanoma. In this review, we discuss the known molecular aberrations in melanoma, current and novel targeted approaches in its treatment, and drug resistance patterns.