Advanced melanoma remains a largely incurable diagnosis. The availability genetic evidence and emerging experimental evidence provides a matrix of oncogenes and signal transduction pathways that have yet to be exploited in terms of development of targeted therapies. BRAF mutant melanoma represents a large subpopulation for which single-agent oncogene targeting has been established and the focus is now to understand the consequences and limits of BRAF inhibition as a way of developing rational combination targeted therapy regimens. Given that 50% of advanced melanoma patients are BRAF wild-type establishing foundation of single-agent or combination targeted therapies in this large and heterogeneous subgroup is a current unmet need. For BRAF mutant patients, the goals are to circumvent mechanisms of de novo and acquired resistance. My goal is to maintain a portfolio of clinical trials with novel, targeted therapies to validate points of vulnerability nominated by preclinical investigations. In the context of those trials, we are focused on acquiring tumor biopsies to validate the molecular mechanism of each novel agent. Given the inability to safely biopsy all patients on research protocols, we are equally focused on credentialing blood-based biomarkers and novel non-invasive imaging methods for establish proof-of-mechanism and understanding heterogeneity in molecular response. Interrogating patient tumor samples to establish the role of candidate biomarkers in determining responsiveness or resistance is the focus of bedside to bench translational studies. This approached has allowed us to define several novel features of BRAF inhibitor associated resistance factors and downstream consequences.