Cells in vivo grow in mechanically compliant, structurally complex matrices formed by filamentous protein networks, often interspersed with flexible polysaccharide polymers and other macromolecules. As a result, the cells within these materials, or adhering to their surfaces, function in a microenvironment where mechanical properties, electrical conductivity, and chemical conditions can change rapidly, as the result of blood pressure, gravitational forces, and other mechanical stresses or more gradually as the result of normal development, aging, or the onset of disease. New developments in making magnetorheological soft substrates that reversibly change elastic modulus over a large range on a very fast time scale, and electrically conductive substrates with elastic moduli close to those of many soft tissues, including the brain, have the potential to increase understanding of how cells function under the physiological and pathophysiological conditions they encounter in vivo.