A common feature of many solid tumors and is that they are stiffer than the normal tissue in which they arise and have increased interstitial fluid pressures and solid tissue stress. These physical changes, which often involve increased synthesis and cross-linking of extracellular matrix protein, can lead to deleterious changes in mechanosensitive cells.Brain and other CNS tissues lack the filamentous protein-based extracellular matrix characteristic of most mesenchymal and epithelial environments, and isolated glioma samples have the same shear storage moduli as normal brain when measured ex vivo at low strains. However, the shear moduli of both normal and malignant brain tissue increase to the kPa range that activates glioma cells and normal glial cells in vitro when the tissue is uniaxially compressed. We suggest that compression stiffening, which might occur with the increased vascularization and interstitial pressure gradients that are characteristic of glioma and other tumors, effectively stiffens the environment of glioma cells and that in situ, the elastic resistance these cells sense might be sufficient to trigger the same responses that are activated in vitro by increased substrate stiffness.