Physical forces have a crucial role in tumor progression and cancer treatment. The application of principles of engineering and physical sciences to oncology has provided powerful insights into the mechanisms by which these forces affect tumor progression and confer resistance to delivery and efficacy of molecular, nano-, cellular, and immuno-medicines. Here, we discuss the mechanics of the solid and fluid components of a tumor, with a focus on how they impede the transport of therapeutic agents and create an abnormal tumor microenvironment (TME) that fuels tumor progression and treatment resistance. We also present strategies to reengineer the TME by normalizing the tumor vasculature and the extracellular matrix (ECM) to improve cancer treatment. Finally, we summarize various mathematical models that have provided insights into the physical barriers to cancer treatment and revealed new strategies to overcome these barriers.