The study of cellular responses to endogenous mechanochemical stimuli in situ is often stymied by technical challenges. However, bioengineered in vitro models have simulated in vivo conditions and produced significant breakthroughs in our understanding of cellular and molecular processes. This presentation focuses on custom-made hardware and software designed to model specific aspects of tumor biology. These systems emphasize three-dimensional substrates, physiologic conditions for long-term cell culture, automation, and compatibility with time-lapse imaging. A fully automated system, which tracks 3D cellular motion in combination with statistical analysis of the cell trajectories, has enabled measurements of the migratory and invasive potential for various types of tumor cells. This system can be used as a screening tool for cancer motility and potentially therapeutic drugs. Time-lapse analysis also revealed that defects in collagen polymerization differentially affect the 3D migration of mammary carcinoma cells by enhancing their morphodynamic activity and promoting motility and invasion. Another model system, the 3D cell-pressor, was developed to simulate the stress built-up in a growing tumor and allowed quantification of the effects of mechanical compression on cancer cell morphology, metastatic potential, and in vivo aggressiveness. Another system, the time-lapse analysis chamber for laser capture microdissection (LCM), enables time-lapse topography of differentiating cell cultures and pre-selection of cell targets thus minimizing LCM time and optimizing the quality of isolated biomolecules for genomics and proteomics analyses. The first ever application of LCM in living 3D cultures, led to identification of molecules that could enable autopoiesis of vascular-like networks by melanoma cells with potentially significant clinical implications, such as response to anti-angiogenic treatments. Overall these systems, used independently or in tandem, provide discovery engines that enable novel insights into the interplay and the individual roles of tumor cells and mechanochemical components of the microenvironment in the process of cancer metastasis.