Control of mesangial cell growth and matrix accumulation is critical for normal development of the glomerular tuft and progression of glomerular injury, but the genes that control mesangial cell growth are not well understood. We used high-density oligonucleotide microarrays to analyze gene expression in well-differentiated human mesangial cells treated with serum to stimulate proliferation. Parallel measurement of >12,000 genes and expressed sequence tags identified 5,806 mRNA transcripts in quiescent, unstimulated cells and 609 genes significantly induced or repressed by serum. Functional classification of serum-regulated genes revealed many genes not directly related to cell cycle progression that, instead, might control renal hemodynamics and glomerular filtration or cause tissue injury, leukocyte exudation, matrix accumulation, and fibrosis. Hierarchical cluster analysis defined sets of coregulated genes with similar functions and identified networks of proinflammatory genes with similar expression patterns. Pathway analysis of the gene expression profile suggested an autocrine role in mesangial cell proliferation for three growth factors in the epidermal growth factor (EGF) family: heparin-binding EGF-like growth factor, amphiregulin, and epiregulin. A functional role for EGF receptor (EGFR) activation was confirmed by blocking serum-induced proliferation with an EGFR-selective kinase inhibitor and a specific EGFR-neutralizing antibody. Taken together, these results suggest a role for EGFR signaling in control of mesangial cell growth in response to serum.