Smooth muscle-specific transcription is controlled by a multitude of transcriptional regulators that cooperate to drive expression in a temporal-spatial manner. Previous analysis of the cysteine-rich protein 1 (CRP1/Csrp) gene revealed an intronic enhancer that is sufficient for expression in arterial smooth muscle cells, and requires a serum response factor-binding CArG element for activity. The presence of a CArG box in smooth muscle regulatory regions is practically invariant, however it stands to reason that additional elements contribute to the modulation of transcription in concert with the CArG. Because of the potential importance of other regulatory elements for expression of the CRP1 gene, we sought to identify additional motifs within the enhancer that are necessary for expression. In this effort, we identified a conserved cyclic AMP response element (CRE) that when mutated diminishes the expression of the enhancer in cultured vascular smooth muscle cells. Using transfection and electromobility shift assays, we show that the CRE binds the cyclic AMP response element-binding protein (CREB), and is activated by calcium/calmodulin-dependent protein kinase (CaMK) IV, but not by CaMKII. Further, our data demonstrates that CaMKIV stimulates CRP1 expression, not only through the CRE, but also through the CArG box. These findings represent evidence of a functional CRE within a smooth muscle-specific gene, and provide support for a mechanism in which CREB functions as a smooth muscle determinant through CaMKIV activation.