Cell homeostasis and diverse processes, including migration, are tightly regulated by cell volume. In vivo, metastatic tumor cells must navigate complex, heterogeneous microenvironments when migrating through tissues, including longitudinal tracks formed by anatomic structures. Intriguingly, we have discovered that the classical model of cell migration on two-dimensional substrates (relying on actin polymerization, cell adhesion to the substrate, and myosin II-mediated contractility) does not apply to metastatic tumor cells migrating through three-dimensional confined spaces. We therefore hypothesized that an alternate mechanism based on cell volume regulation via ion channels and aquaporins drives cell migration in these confined microenvironments, where cells must deform in order to squeeze through physically restrictive spaces. Using a multidisciplinary approach that integrates microfabrication techniques, molecular biology, live cell imaging, and theoretical modeling based on physics, we have developed an “Osmotic Engine Model” of cell migration, which demonstrates that osmotically-driven water flow regulates cell migration in confined microenvironments. Importantly, our theoretical model predicts many key non-intuitive experimental results. Collectively, this study represents a new paradigm for cell migration in confined microenvironments and elucidates ion pumps and aquaporins as new molecular targets that may be exploited for future development of cancer therapeutics.