The majority of cancer-related deaths are due to metastasis. The failure to develop efficient anti-metastatic drugs has been attributed to an incomplete understanding of the biological mechanisms that drive metastasis. However, mechanical cues have recently emerged as contributors to tumor development and progression. One of the main physical hallmarks of cancer is elevated extracellular matrix stiffness, which alters tumor cell proliferation, survival, contractility, deformability, and migration. Moreover, recent evidence shows that human cells that change their behavior in response to a certain physical microenvironment have the ability to maintain this behavior even after withdrawal of the original physical stimulus and exposure to a new microenvironment, a concept called “cell mechanical memory”. Bringing these ideas together, we hypothesize that the stiffness-induced biophysical adaptations that are imprinted on tumor cells in the primary tumor microenvironment are retained throughout the metastatic process via mechanical memory, and enhance tumor cell extravasation, survival, and colonization in the metastatic organ. This talk will cover our ongoing investigation of the role of cell mechanical memory in cancer metastasis using microfluidic models of human microvasculature and mouse models. We will also discuss how deciphering mechanisms of mechanical memory formation and retention, including persistent epigenetic changes, can power the discovery of a new class of anti-metastatic drugs.