Cardiac tissue is composed of cardiomyocytes, vascular cells, fibroblasts, and extracellular matrix (ECM). Myocardial cell death due to cellular injury, such as acute myocardial infarction, triggers a multistage repair response in which the damaged tissue is replaced by a fibrotic scar, mainly composed of ECM produced by myofibroblasts. In the heart, it is believed that most myofibroblasts are transdifferentiated from resident cardiac fibroblasts. Although the initial reparative fibrosis is critical to prevent ventricular wall rupture, an excessive fibrotic response is detrimental. This is because sustained activation of myofibroblasts leads to excessive ECM deposition, which reduces cardiac contractile properties and disturbs cardiac electrical signaling, resulting in heart failure. Therefore, myofibroblast regulation may be a potential target for heart failure therapy. In this section, we discuss cardiac fibrosis with a focus on myofibroblasts and present our work on 2,5-dimethylecoxib which is a promising new anti-fibrotic agent. We hope that our discussion of the relationship between cardiac fibrosis and myofibroblasts will lead to the development of new anti-fibrotic agents and the treatment of heart failure.