Fibroblasts are the predominant cell type in the cardiac interstitium. As the 
main matrix-producing cells in the adult mammalian heart, fibroblasts maintain 
the integrity of the extracellular matrix network, thus preserving geometry and 
function. Following myocardial infarction fibroblasts undergo dynamic phenotypic 
alterations and direct the reparative response. Due to their strategic location, 
cardiac fibroblasts serve as sentinel cells that sense injury and activate the 
inflammasome secreting cytokines and chemokines. During the proliferative phase 
of healing, infarct fibroblasts undergo myofibroblast transdifferentiation 
forming stress fibers and expressing contractile proteins (such as α-smooth 
muscle actin). Mechanical stress, transforming growth factor (TGF)-β/Smad3 
signaling and alterations in the composition of the extracellular matrix induce 
acquisition of the myofibroblast phenotype. In the highly cellular and growth 
factor-rich environment of the infarct, activated myofibroblasts produce matrix 
proteins, proteases and their inhibitors regulating matrix metabolism. As the 
infarct matures, "stress-shielding" of myofibroblasts by the cross-linked matrix 
and growth factor withdrawal may induce quiescence and ultimately cause 
apoptotic death. Because of their critical role in post-infarction cardiac 
remodeling, fibroblasts are promising therapeutic targets following myocardial 
infarction. However, the complexity of fibroblast functions and the 
pathophysiologic heterogeneity of post-infarction remodeling in the clinical 
context discourage oversimplified approaches in clinical translation. This 
article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac 
Pathways of Differentiation, Metabolism and Contraction.