Cell migration and invasion are essential in physiological processes (development, immune system function, wound healing, angiogenesis) and also in pathologies such as cancer metastasis. Some cancer cells migrate away from the primary tumour mass and invade into surrounding tissue, intravasate into vasculature and eventually colonize other organ(s), developing metastasis. Cell motility is driven by Rho GTPase signalling, which controls the cell cytoskeleton through regulation of actin polymerization and actomyosin contractility; both are essential for cell movement to take place. High Myosin II activity, indicative of high actomyosin contractility, is found in the invasive edge of cutaneous melanomas, suggesting that these cells with high Myosin II activity are the ones that will most likely disseminate and eventually develop metastasis. Therefore, efforts should be focused on targeting these cells by blocking Myosin II activity. In fact, Myosin II contributes to resistance to MAPK-targeted therapies and also immune checkpoint inhibitor-based therapies in melanoma. Importantly, blocking Myosin II activity overcomes therapy resistance in melanoma. Our lab is focused on investigating how the cytoskeleton, and in particular Myosin II, is regulated during melanoma progression and also during adaptation to therapy, with the aim of finding novel actionable targets.