This chapter reviews the mechanical properties of prominent matrix proteins and the nature of cell attachments to the matrix. The chapter discusses the process of interaction of cell-matrix attachments with the cytoskeleton to regulate stretch sensitivity of mechanosensitive channels, and analyzes the process that matrix proteins may interact with mechanosensors to affect mechanotransduction. Mechanosensation involves the ability of cells to detect forces and explore the topography of the extracellular matrix. This information about the physical environment is then translated into intracellular biochemical signals, a process known as “mechanotransduction” that leads to the generation of cellular responses (mechanoresponses) that may impact the structure and function of the extracellular matrix itself. Target cell adaptation and desensitization of mechanosensitive channels to constant or repeated mechanical stimulation in connective tissue fibroblasts has been reported and may prevent “information overload” including overt Ca2+ induced cell death. Cellular adaptations to applied mechanical forces, including the regulation of mechanosensitive channel function, is important for optimizing cellular responses to fluctuations in the physical environment of cells.