Connective tissue growth factor (CTGF, CCN2) is a secreted matricellular protein, the functions of which depend on the interactions with other molecules in the microcellular environment. As an example of context‐dependent activity of CTGF, this review will outline different aspects of CTGF function in relation to angiogenesis. CTGF is barely expressed in normal adult tissue, but is strongly upregulated in fibrotic tissue and is also increased during development, in wound healing, or in certain types of cancer. Accordingly, gene expression of CTGF is tightly regulated. To highlight the complexity of the regulation of CTGF gene expression, we discuss here the mechanisms involved in CTGF regulation by TGFbeta in different cell types, and the mechanisms related to CTGF gene expression in cells exposed to mechanical forces. Finally, we will touch upon novel aspects of epigenetic regulation of CTGF gene expression. © 2009 International Union of Biochemistry and Molecular Biology, Inc.