The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events. In melanomas, dysregulation of the MAPK pathway occurs frequently due to activating mutations in the B-RAF and RAS genes or other genetic or epigenetic modifications, leading to increased signaling activity promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. However, identification of ideal pathway member to therapeutically target for maximal clinical benefit to melanoma patients remains a challenge. This review provides an overview of the obstacles faced targeting the MAPK pathway and why certain therapeutic approaches succeed while others fail. The review summarizes the roles played by the proteins, therapeutic potential and the drugs available to target each member of the pathway as well as concerns related to each. Potential for targeting multiple points and inhibiting other pathways along with MAPK inhibition for optimal efficacy are discussed along with explanations for development of drug resistance, which includes discussions related to cross-talk between pathways, RAF kinase isoform switching and phosphatase deregulation. Finally, the use of nanotechnology is reviewed as an approach to target the MAPK pathway using both genetic and pharmacological agents simultaneously targeting multiple points in the pathway or in combination with other cascades.