Cell migration plays a pivotal role in diverse (patho)physiological phenomena, including cancer metastasis. Our knowledge on the mechanisms of cell motility originates primarily from studies using unconfined, two-dimensional (2D) substrates. However, these 2D assays fail to recapitulate the confining tracks encountered in vivo. Thus, we have engineered in vitro models to study cell motility in confining channels of different stiffness. This presentation will focus on the plasticity of cancer cell migration mechanisms, and how cells sense, adapt and respond to different physical microenvironments. The seminar will also discuss how this knowledge led to the development of a microchannel assay capable of predicting a cancer patient’s risk of metastasis.