Molecularly targeted cancer treatment has become an achievable goal thanks to systematic analysis of cancer genome as well as development of highly selective tumor targeted drugs. In many human cancers, deregulation of the RTK/RAS/MAPK pathway is the driving force of the disease. Indeed, cancer cells become addicted to such signaling, rendering them susceptible to drugs that can intercept growth factor signaling cascade at different levels. Discovery of mutations or aberrant expression of components of this cascade in radio- and chemotherapy refractory human melanoma acted as an enormous stimulus for scientist to try to identify and clinically test new therapeutic approaches blocking the RTK/RAS/MAPK cascade. These efforts not only resulted in the identification of new drugs for melanoma treatment but also in a better understanding of molecular basis of primary and secondary resistance to targeted therapies.