A fundamental question in cell biology is how cells regulate the synthesis and construction of tissue-specific extracellular matrices (ECMs) in their environment and, in turn, how changes in the structure and composition of the ECM can influence cell behavior in response to injury and disease. In particular, we are interested in cellular mechanisms of collagen fibril assembly in the ECM and the function of matricellular proteins in the regulation of this process. Matricellular proteins are defined as proteins that associate with the ECM but do not contribute structurally to the ECM in contrast to classical ECM proteins such as collagen and laminin. We have established that one matricellular protein, SPARC (secreted protein acidic and rich in cysteine, osteonectin, BM-40), influences the formation of collagen I fibers in connective tissues of mice. For example, collagen accumulation associated with pressure-overload hypertrophy is significantly reduced in SPARC-null mice. Elucidation of pathways by which SPARC and other collagen binding proteins influences collagen incorporation and stability in the ECM can lead to the design of strategies to control fibrotic processes in the heart and in other tissues. Alternatively, in diseases in which collagenous tissue is degraded, such as in periodontal disease, factors that improve collagen assembly are useful tools to improve strategies to restore damaged tissues.