Melanoma has been one of the fastest rising malignancies in the last four decades with cases increasing from below 3 per 100,000 people to above 13. Despite worldwide efforts in prevention, diagnosis, and treatment, cases of melanoma continue to rise at an alarming rate of 2.5% annually in the United States. Although early primary melanomas are curable through surgery, treatment of advanced disease remains difficult and the strategies employed in the last 30 years have not significantly improved cure rates, which are less than 5%. The recent identification of activating mutations in BRAF in over 60% of cases of melanoma has caused much excitement in the melanoma community and may offer the first opportunity for a rational treatment program. Combination therapy using the RAF inhibitor, BAY 43-9006, and chemotherapy has led to impressive responses in some melanoma patients and provides a new paradigm for therapeutic intervention in this intractable disease. Besides activating mutations in BRAF, melanomas have constitutive activity in a number of other signaling pathways implicated in oncogenesis, including PI3 kinase/Akt, NFB, Src, and STAT3. With more and more selective small molecule inhibitors becoming available, there are good prospects for treating advanced melanoma using new combinations of signal transduction inhibitors and chemotherapy. In the current review, we discuss the role for these signaling pathways in melanoma and discuss the rationale for targeting signaling cascades using small molecule inhibitors.