Purpose of review: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients. Recent findings: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. Summary: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.