The extracellular matrix is the major constituent of organic matter in both plants and animals, where it provides the interface between individual cells. In most tissues, with some notable exceptions such as bone marrow, the volume of extracellular matrix equals or exceeds the volume of intracellular space and organelles, making matrix an abundant constituent through which cells exert their functions and receive cues. The matrix may therefore be considered the basic structural entity that supports the function of an organ, and in connective tissues the matrix is the organ itself to which function is tied throughout the life of its resident cells. In this review, a select number of proteinases involved in some of the more conspicuous matrix remodeling events of the mammalian organism are explored. Evidence from both animal models and human diseases is discussed in relation to normal physiological processes, including instances in which aberrant matrix remodeling leads to disease states. Birth Defects Research (Part C) 78:11–23, 2006. © 2006 Wiley-Liss, Inc.