Cysteine‐rich protein 61 (Cyr61/CCN1) is an angiogenic factor and a member of a family of growth factor‐inducible immediate‐early genes with functions in cell adhesion, proliferation and differentiation. We investigated the regulatory mechanisms and signaling pathways involved in Cyr61/CCN1gene activation in smooth muscle cells. Treatment of these cells with sphingosine 1‐phosphate (S1P), a bioactive lysolipid, increased rapidly but transiently the expression of the Cyr61/CCN1 gene at both the mRNA and protein levels. Cyr61/CCN1 mRNA stability was not altered but the transcription rate of the Cyr61/CCN1 gene was increased fivefold in isolated nuclei from S1P‐stimulated cells indicating that the level of control is primarily transcriptional. Transfection experiments showed that a 936‐bp promoter fragment of the human Cyr61/CCN1 gene is functional and induces a reporter gene activity in S1P‐treated cells. Using a combination of cis‐element mutagenesis and expression of dominant negative inhibitors of transcription factors, we showed that both a CRE and AP‐1 site and their cognate transcription factors, cAMP response element binding protein (CREB) and AP‐1, were responsible for the promoter activity in S1P‐stimulated cells. Furthermore, by using either pharmacological inhibitors or active forms of known signaling molecules, we showed that inducible Cyr61/CCN1 gene expression occurs through RhoA GTPase and that additional signaling through the p38 pathway is required. In particular, p38 seems to regulate Cyr61/CCN1 promoter activity through modulation of phosphorylation of CREB and the CREB kinase, MSK1. These findings demonstrate the transcriptional regulation of the Cyr61/CCN1 gene and provide clues to the signaling molecules and transcription factors involved in such regulation.