The cardiovascular restricted transcription factor CHF1/Hey2 has been previously shown to regulate the smooth muscle response to growth factors. To determine how CHF1/Hey2 affects the smooth muscle response to growth factors, we performed a genomic screen for transcripts that are differentially expressed in wild-type and knockout smooth muscle cells after stimulation with platelet-derived growth factor. We screened 45,101 probes representing >39,000 transcripts derived from at least 34,000 genes, at eight different time points. We analyzed the expression data utilizing an algorithm based on Bayesian statistics to derive the best polynomial clustering model to fit the expression data. We found that in a total of 9,827 transcripts the normalized ratio of knockout to wild-type expression diverged more than threefold from baseline in at least one time point, and these transcripts separated into 17 distinct clusters. Further analysis of each cluster revealed distinct alterations in gene expression patterns for immediate early genes, transcription factors, matrix metalloproteinases, signaling molecules, and other molecules important in vascular biology. Our findings demonstrate that CHF1/Hey2 profoundly affects vascular smooth muscle phenotype by altering both the absolute expression level of a variety of genes and the kinetics of growth factor-induced gene expression.