Physical cues have emerged as critical influencers of cell function during physiological processes, like development and organogenesis, and throughout pathological abnormalities, including cancer progression and fibrosis. While ion channels have been implicated in maintaining cellular homeostasis, their cell surface localization often places them among the first few molecules to sense external cues. Mechanosensitive ion channels (MICs) are especially important transducers of physical stimuli into biochemical signals. In this review, we describe how physical cues in the tumor microenvironment are sensed by MICs and contribute to cancer metastasis. First, we highlight mechanical perturbations, by both solid and fluid surroundings typically found in the tumor microenvironment and during critical stages of cancer cell dissemination from the primary tumor. Next, we describe how Piezo1/2 and transient receptor potential (TRP) channels respond to these physical cues to regulate cancer cell behavior during different stages of metastasis. We conclude by proposing alternative mechanisms of MIC activation that work in tandem with cytoskeletal components and other ion channels to bestow cells with the capacity to sense, respond and navigate through the surrounding microenvironment. Collectively, this review provides a perspective for devising treatment strategies against cancer by targeting MICs that sense aberrant physical characteristics during metastasis, the most lethal aspect of cancer.