Living cells are complex entities whose remarkable, emergent capacity to sense, integrate, and respond to environmental cues relies on an intricate series of interactions among the cell's macromolecular components. Defects in mechanosensing, transduction,or responses underlie many diseases such as cancers, immune disorders, cardiac hypertrophy, genetic malformations, and neuropathies. Here, we highlight micro- and nanotechnology-based tools that have been used to study how chemical and mechanical cues modulate the responses of single cells in contact with the extracellular environment. Understanding the physical aspects of these complex processes at the micro- and nanometer scale could produce profound and fundamental new insights into how the processes of cell migration, metastasis, immune function and other areas which are regulated by mechanical forces.