Nerve tissue comprises a variety of cells, blood vessels, and extracellular matrix. All of these building blocks differ in their mechanical properties; therefore, particularly during growth and migration, the local mechanical environment of motile CNS cells will change considerably. Here we show that both neurons and glial cells, the basic building blocks of nerve tissue, respond to these variations in their mechanical microenvironment. Using culture substrates incorporating gradients of mechanical properties we found that neuronal axons are repelled by stiff substrates while glial cells spread more on stiffer substrates. We have used traction force microscopy and scanning force microscopy in combination with calcium imaging to suggest a possible model for neuronal mechanosensing. During development, this mechanosensitivity might be used - in combination with biochemical signaling - to guide neuronal axons along distinct pathways. Glial cell reactivity, on the other hand, which is found in numerous pathological processes, is also triggered by mechanical cues. Neural implants for example, which are orders of magnitude stiffer than healthy CNS tissue, often cause a foreign body reaction, which is characterized by an encapsulation of the implant by reactive microglial cells and later by reactive astrocytes. This assembly of different glial cell layers around the 'foreign body' results in a serious reduction of lifetime and functionality of these devices. The mechanical mismatch between implant and tissue may trigger the encapsulation of the implant, repelling neurons while attracting glial cells. Exploiting this knowledge may ultimately lead to the development of a new generation of implants, incorporating appropriate mechanical cues which support healthy tissue structure.