The transcriptional coactivator p300 is a ubiquitous nuclear phosphoprotein and transcriptional cofactor with intrinsic acetyltransferase activity. p300 controls the expression of numerous genes in cell-type and signal-specific manner, and plays a pivotal role in cellular proliferation, apoptosis, and embryogenesis. By catalyzing acetylation of histones and transcription factors, p300 plays a significant role in epigenetic regulation. Recent evidence suggests that abnormal p300 function is associated with deregulated target gene expression, and is implicated in inflammation, cancer, cardiac hypertrophy, and genetic disorders such as the Rubinstein-Taybi syndrome. The activity of p300 is regulated at multiple levels, including developmental stage-specific expression, post-translational modifications, subcellular localization, and cell-type and gene-specific interactions with transcription factors. Although p300 has been investigated extensively in epithelial and hematopoietic cells, its role in fibroblast biology and tissue repair has received little attention to date. Recent studies implicate p300 in the regulation of collagen synthesis by transforming growth factor-beta (TGF-beta). Both the acetyltransferase activity of p300 and its inducible interaction with Smad3 are essential for mediating TGF-beta-induced stimulation of collagen synthesis. As a signal integrator whose availability for intracellular interactions with transcription factors is strictly limiting, p300 mediates the antagonistic regulation of TGF-beta-induced collagen synthesis by IFN-gamma and TNF-alpha via intracellular competition for limiting amount of p300. Significantly, p300 is itself a direct transcriptional target of TGF-beta in normal fibroblasts, and its levels are significantly elevated in fibrotic lesions as well as in experimental models of fibrosis. The emerging appreciation of the importance of p300 in extracellular matrix (ECM) remodeling and fibrosis and novel insights concerning the regulation, mechanism of action, and significance of p300 in fibroblast biology are discussed in this minireview.