The article discusses the role of Transforming Growth Factor (TGF)-β in cardiac remodeling, particularly in myocardial infarction and cardiac hypertrophy. TGF-β is upregulated in these conditions and plays a crucial role in modulating cardiomyocytes, mesenchymal, and immune cells. It is involved in fibrosis and hypertrophy, with overexpression in the mouse heart leading to fibrosis and hypertrophy. In the infarcted heart, TGF-β deactivates inflammatory macrophages and promotes myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways, acting as a "master switch" for the transition from inflammation to scar formation. The TGF-β system is a promising therapeutic target for heart failure, but its complex and pleiotropic effects, as well as concerns about potential deleterious actions, pose challenges. Understanding specific pathways and cell-specific actions of TGF-β is essential for designing optimal therapeutic strategies. The article also highlights the relationship between TGF-β and the renin-angiotensin system (RAS), and the increased expression of TGF-β in human cardiomyopathy. Finally, it discusses the potential benefits and challenges of targeting the TGF-β system in the failing heart, emphasizing the need for selective inhibition of profibrotic signaling.The article discusses the role of Transforming Growth Factor (TGF)-β in cardiac remodeling, particularly in myocardial infarction and cardiac hypertrophy. TGF-β is upregulated in these conditions and plays a crucial role in modulating cardiomyocytes, mesenchymal, and immune cells. It is involved in fibrosis and hypertrophy, with overexpression in the mouse heart leading to fibrosis and hypertrophy. In the infarcted heart, TGF-β deactivates inflammatory macrophages and promotes myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways, acting as a "master switch" for the transition from inflammation to scar formation. The TGF-β system is a promising therapeutic target for heart failure, but its complex and pleiotropic effects, as well as concerns about potential deleterious actions, pose challenges. Understanding specific pathways and cell-specific actions of TGF-β is essential for designing optimal therapeutic strategies. The article also highlights the relationship between TGF-β and the renin-angiotensin system (RAS), and the increased expression of TGF-β in human cardiomyopathy. Finally, it discusses the potential benefits and challenges of targeting the TGF-β system in the failing heart, emphasizing the need for selective inhibition of profibrotic signaling.