Many cell types, including neurons and glial cells, respond strongly to changes in matrix rigidity when cultured on flexible substrates. Neurons are very unusual in that they extend processes and survive better on very soft materials than they do on stiff surfaces. In contrast, on soft gels astrocytes remain unactivated, do not spread, and have disorganized F-actin and intermediate filament systems compared to the cytoskeletons of astrocytes on hard surfaces. The stiffness range over which these cell types alter their phenotype is in the range from 50 Pa to 2000 Pa, approximately the range of elastic modulus for intact brain, when measured at small strains on a time scale of 1 s. The effects of substrate stiffness are evident when cells are grown on synthetic gels made from flexible rubberlike polymers or when they are embedded in semi-flexible biopolymer gels such as fibrin. The different responses of neurons and astrocytes enables preferential selection of cell type by altering matrix stiffness. Dissociated embryonic rat cortices grown on flexible fibrin gels, a biomaterial with potential use as an implant material, display a similar mechano-dependent difference in cell population. These data emphasize the potential importance of material substrate stiffness as a design feature in the next generation of biomaterials intended to promote neuronal regeneration across a lesion in the CNS while simultaneously minimizing the ingrowth of astrocytes into the lesion area. The length and time scales over which cells deform their substrate and alter their morphology suggest mechanisms by which these cells can sense mechanical signals.