Simple SummaryMetastatic melanoma is the most lethal skin cancer due to its high metastatic potential and resistance to treatment. The advent of targeted therapies has improved patient management. However, due to the emergence of resistance shortly after the start of treatment, the overall and progression-free survival remain limited. In this review, we aim to update recent published data about metastatic melanoma, its therapeutic management, and the associated resistance mechanisms involved in disease relapse. We describe recent data on cellular and microenvironment-induced resistance to targeted therapies. The discovery of targetable mutations and the understanding of the mechanisms involved in the development of metastatic melanoma has allowed for the improvement in patient treatments thanks to targeted therapies and immune checkpoint inhibitors. Further understanding of other non-elucidated mechanisms of resistance will contribute to improving melanoma patients’ management.AbstractMelanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.