Most tissue cells must adhere to a solid for viability, and such aspects of microenvironment appear particularly important in Stem Cell differentiation. Adult Mesenchymal Stem Cells are shown to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain prove neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. Inhibition of nonmuscle myosin II blocks all elasticity directed lineage specification, highlighting the role of cell-generated stress. The results have significant implications for stem cells in regenerative strategies. The results have also motivated development of an in-cell method to tag proteins that unfold in stressed cells; the fluorescent tags allow imaging of distributions as well as Mass Spec identification and quantification on a proteomic scale.