In the adult organism, the cellular microenvironment is critical in controlling cell growth, death, or regeneration. Although the fluid microenvironment includes several factors that influence cells, such as nutrients, salts, and hormones, we will focus here on the extracellular matrix and neighboring cells. The cellular microenvironment must support the tissue functions in the organism and should enable cell turnover and repair. Repair necessitates controlled growth to the proper cell density relative to matrix; however, safeguards are then needed to avoid uncontrolled growth, which can result in cancer. In this chapter, we will discuss the organizing principles in (1) cell–matrix interactions, (2) cell–cell interactions, and (3) the interplay between the two. In the case of the extracellular matrix (ECM), the composition of the ECM and its architecture sets the program for the adjacent cells through both the chemical nature of the ECM molecules and the shape of the crosslinked matrices in the adult. The detergent-resistant matrix of a tissue contains a lot of information that can direct the regeneration of stem cells when added to the matrix. In addition, the ECM will direct the cellular repair process following the loss of individual or small numbers of cells and the mechanical characteristics are critical. Matrix provides mechanical support through basement membranes, ECM fibrous networks, or linear fibers. The number of cells in the given matrix will be set by the physical aspects of the cell–cell contacts and the amount of ECM available. In the case of cell–cell junctions, there is a more limited set of components in adhesions, but some of the same cytoskeletal elements are important. Again, mechanical signals derived from the reciprocal communication between neighboring cells as well as the matrix are critical for directing the growth of the organism and controlling repair processes. Most importantly, the cell must only grow in an environment that is defined by a combination of cell neighbors, the matrix as well as nutrients and hormones. If the cell doesn't respond properly to the local cell and matrix cues, then it is likely that dysfunction will result. Major trauma and damage in the adult is usually bandaided with collagen fibers that cover the damage site (scar tissue) but do little to restore normal function in that region.