Cardiac fibrosis, characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium, distorts the architecture of the myocardium, facilitates the progression of arrhythmia and cardiac dysfunction, and influences the clinical course and outcome in patients with heart failure. This review describes the composition and homeostasis in normal cardiac interstitial matrix and introduces cellular and molecular mechanisms involved in cardiac fibrosis. We also characterize the ECM alteration in the fibrotic response under diverse cardiac pathological conditions and depict the role of matricellular proteins in the pathogenesis of cardiac fibrosis. Moreover, the diagnosis of cardiac fibrosis based on imaging and biomarker detection and the therapeutic strategies are addressed. Understanding the comprehensive molecules and pathways involved in ECM homeostasis and remodeling may provide important novel potential targets for preventing and treating cardiac fibrosis.