Transforming Growth Factor (TGF)-β signaling plays a critical role in cardiac remodeling and fibrosis. TGF-β is upregulated in experimental models and patients with heart failure, cardiac hypertrophy, and cardiomyopathies. It influences cardiomyocytes, mesenchymal, and immune cells, contributing to fibrosis and hypertrophy. TGF-β signaling is essential for the transition from the inflammatory phase to scar formation in the infarcted heart. However, its complex and pleiotropic effects, along with potential adverse effects of inhibition, complicate therapeutic strategies. TGF-β is involved in matrix metabolism, fibroblast function, and myofibroblast transdifferentiation. It also interacts with the renin-angiotensin system, which is crucial for cardiac remodeling. TGF-β signaling is regulated by various pathways, including Smad3, which is critical for fibrogenic actions. TGF-β inhibition can have beneficial effects in certain contexts but may also lead to adverse outcomes. Understanding the specific roles of TGF-β isoforms and their signaling pathways is essential for developing targeted therapies. Future research should focus on dissecting TGF-β pathways, understanding its effects on different cell types, and exploring its role in high-risk populations. Targeting TGF-β signaling may offer therapeutic benefits in heart failure and cardiomyopathies, but careful consideration of its complex functions is necessary to avoid unintended consequences.Transforming Growth Factor (TGF)-β signaling plays a critical role in cardiac remodeling and fibrosis. TGF-β is upregulated in experimental models and patients with heart failure, cardiac hypertrophy, and cardiomyopathies. It influences cardiomyocytes, mesenchymal, and immune cells, contributing to fibrosis and hypertrophy. TGF-β signaling is essential for the transition from the inflammatory phase to scar formation in the infarcted heart. However, its complex and pleiotropic effects, along with potential adverse effects of inhibition, complicate therapeutic strategies. TGF-β is involved in matrix metabolism, fibroblast function, and myofibroblast transdifferentiation. It also interacts with the renin-angiotensin system, which is crucial for cardiac remodeling. TGF-β signaling is regulated by various pathways, including Smad3, which is critical for fibrogenic actions. TGF-β inhibition can have beneficial effects in certain contexts but may also lead to adverse outcomes. Understanding the specific roles of TGF-β isoforms and their signaling pathways is essential for developing targeted therapies. Future research should focus on dissecting TGF-β pathways, understanding its effects on different cell types, and exploring its role in high-risk populations. Targeting TGF-β signaling may offer therapeutic benefits in heart failure and cardiomyopathies, but careful consideration of its complex functions is necessary to avoid unintended consequences.