Extracellular nucleotides are potent mediators of cardiovascular physiologic and pathologic responses, contributing to the inflammatory and fibrotic milieu within the injured myocardium. Via autocrine or paracrine signaling, extracellular nucleotides and nucleosides elicit cell-specific effects through differentially expressed purinergic receptors of the P2X, P2Y, and P1 families. The scale and duration of purinergic signaling is regulated by extracellular nucleotidases that hydrolyze released nucleotides. Here we summarize the data for the role of purinergic pathway in cardiac fibrosis.