The prevalence of heart failure is rising with poor prognosis and health costs. Cardiac remodeling is a cardinal process mediating the progression to heart failure, and cardiac fibroblasts play a critical role in the regulation of left ventricular remodeling mainly through the excessive extracellular matrix protein deposition and their differentiation to a myofibroblast phenotype with excessive proliferative and migratory properties. All this characteristics are known also as cardiac fibrosis. This process is crucial for the structural integrity of myocardial tissue. After myocardial infarction, are activated two important type of cardiac fibrosis: reparative and reactive cardiac fibrosis. Both of them are mediated by a huge number of inflammatory and hormonal mediators. In this review we will focus on the role of three important systems involved in cardiac fibrosis and described as the great contributors in heart failure: inflammatory, RAA and beta-adrenergic system. The deeper understanding of these great contributors is of interest in the development of new therapeutic strategies toward cardiac fibrosis and heart failure.