As tumor cells metastasize from the primary tumor location to a distant secondary site, they encounter an array of biologically and physically heterogeneous microenvironments. While it is well established that biochemical signals guide all stages of the metastatic cascade, mounting evidence indicates that physical cues also direct tumor cell behavior, including adhesion and migration phenotypes. Physical cues acting on tumor cells in vivo include extracellular matrix mechanical properties, dimensionality, and topography, as well as interstitial flow, hydrodynamic shear stresses, and local forces due to neighboring cells. State-of-the-art technologies have recently enabled us and other researchers to engineer cell microenvironments that mimic specific physical properties of the cellular milieu. Through integration of these engineering strategies, along with physics, molecular biology, and imaging techniques, we have discovered new insights into tumor cell adhesion and migration mechanisms. In this review, we focus on the extravasation and invasion sections of the metastatic cascade. We first discuss the physical role of the endothelium during tumor cell extravasation and invasion, and how contractility of both endothelial and tumor cells contributes to the ability of tumor cells to exit the vasculature. Next, we examine how matrix dimensionality and stiffness co-regulate tumor cell adhesion and migration beyond the vasculature. Finally, we summarize how tumor cells translate and respond to physical cues through mechanotransduction. Due to the critical role of tumor cell mechanotransduction during the metastatic cascade, targeting signaling pathways involved in tumor cell mechano-sensing of physical stimuli may prove to be an effective therapeutic strategy for cancer.