The CCN family of matricellular signaling regulators shares a common domain structure. Variants of individual CCN proteins exist, which contain different combinations of these domains. Although mRNA splicing is likely to play a key role on CCN biology, this hypothesis has not been thoroughly tested. In a recent report, Hirschfeld and colleagues (Cancer Res 69:2082–90, 2009), show that CCN1 (cyr61) mRNA is normally present in a form in which intron 3 is retained. In cancers, or upon hypoxia, intron 3 is removed resulting in the appearance of CCN1 protein. The significance of this paper is discussed.