Tenascin-C (TN-C) is a modular and multifunctional extracellular matrix (ECM) glycoprotein that is exquisitely regulated during embryonic development and in adult tissue remodeling. TN-C gene transcription is controlled by intracellular signals that are generated by multiple soluble factors, integrins and mechanical forces. These external cues are interpreted by particular DNA control elements that interact with different classes of transcription factors to activate or repress TN-C expression in a cell type- and differentiation-dependent fashion. Among the transcriptional regulators of the TN-C gene that have been identified, the homeobox family of proteins has emerged as a major player. Downstream from TN-C, intracellular signals that are relayed via specific cell surface receptors often impart contrary cellular functions, even within the same cell type. A key to understanding this behavior may lie in the dual ability of TN-C-enriched extracellular matrices to generate intracellular signals, and to define unique cellular morphologies that modulate these signal transduction pathways. Thus, despite the contention that TN-C null mice appear to develop and act normally, TN-C biology continues to provide a wealth of information regarding the complex nature of the ECM in development and disease.