Three dimensional cultures of cells have been used extensively to study cell-matrix interactions. These have included the use of hydrogels, sponges and mixtures of reconstituted matrix proteins such as laminin and fibronectin. The use of artificial matrices consisting of purified matrix proteins does not truly reflect the in vivo micro-environments that contain many other proteins mixed in a defined ratio. A novel in vitro model in use of late involves the use of a natural, cell-derived 3-D matrix that closely mimics the native tissue. As illustrated in this work, which investigated the interaction between fibroblasts and their matrix, there is continuous crosstalk between the two and this has an effect on type I collagen synthesis. Cell-matrix interactions are important in organogenesis, cancer, regenerative medicine as well as in fundamental cell biology. This book provides a comprehensive and systematic investigation into the regulation of type I collagen synthesis and provides evidence that the matrix is not an idle bystander in tissue but is an active participant in cellular processes.