Metastatic melanoma is currently incurable and available therapies, although effective, result in resistance and recurrence. The majority of deaths are due to metastatic disease, highlighting the need for ‘migrastatics’, therapeutics which act to inhibit invasion. A recent paradigm shift positions the extracellular matrix as a key player in the metastatic cascade. Cell navigation of 3D matrix requires adaptive changes in cell and nuclear shape to fit matrix physical attributes in a process termed mechanosensing. This process incorporates dynamic remodelling of cell matrix adhesions and the cytoskeleton, to facilitate movement through confined spaces, via proteolytic matrix degradation or cell squeezing. Microtubules play a pivotal role in both of these processes. Our data show that the microtubule-binding proteins, CLASPs, are highly overexpressed in metastatic melanoma lines where they regulate the resistance of microtubule mechanical compression during melanoma invasion in 3D collagen matrices. Using high-resolution live-cell microscopy coupled to genetic alteration and substrate microfabrication, we have identified that patient-derived Melanoma cells utilise CLASP1 and CLASP2, for differing functions to drive 3D invasion. We report paralog specific depletion of CLASPs results in strikingly different 3D invasion phenotypes. Crucially, paralog specific depletion of CLASPs ablates the ability to inter-convert between adaptive invasion strategies by interfering with microtubule-dependent functions during 3D-invasion. Furthermore, pan-depletion of CLASPs within 1205Lu melanoma cells results in 3D migration stasis and reduced cell viability following conditions of 3D confinement, which we do not observe in 2D. These findings suggest that CLASPs function in melanoma cells to facilitate biomechanically regulated cellular processes of both invasion and survival in confined environments.