Remodeling of the myocardium and the extracellular matrix (ECM) occurs in heart failure irrespective of its initial cause. The ECM serves as a scaffold to provide structural support as well as housing a number of cytokines and growth factors. Hence, disruption of the ECM will result in structural instability as well as activation of a number of signaling pathways that could lead to fibrosis, hypertrophy, and apoptosis. The ECM is a dynamic entity that undergoes constant turnover, and the integrity of its network structure is maintained by a balance in the function of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). In heart disease, levels of MMPs and TIMPs are altered resulting in an imbalance between these two families of proteins. In this review, we will discuss the structure, function, and regulation of TIMPs, their MMP-independent functions, and their role in heart failure. We will review the knowledge that we have gained from clinical studies and animal models on the contribution of TIMPs in the development and progression of heart disease. We will further discuss how ECM molecules and regulatory genes can be used as biomarkers of disease in heart failure patients.