Aberrant epigenetic silencing of tumor suppressor genes by promoter DNA hypermethylation and histone deacetylation plays an important role in the pathogenesis of cancer. The potential reversibility of epigenetic abnormalities encouraged the development of pharmacologic inhibitors of DNA methylation and histone deacetylation as anti-cancer therapeutics. (Pre)clinical studies of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have yielded encouraging results, especially against hematologic malignancies. Recently, several studies demonstrated that DNMT and HDAC inhibitors are also potent angiostatic agents, inhibiting (tumor) endothelial cells and angiogenesis in vitro and in vivo. By reactivation of epigenetically silenced tumor suppressor genes with angiogenesis inhibiting properties, DNMT and HDAC inhibitors might indirectly - via their effects on tumor cells - decrease tumor angiogenesis in vivo. However, this does not explain the direct angiostatic effects of these agents, which can be unraveled by gene expression studies and examination of epigenetic promoter modifications in endothelial cells treated with DNMT and HDAC inhibitors. Clearly, the dual targeting of epigenetic therapy on both tumor cells and tumor vasculature makes them attractive combinatorial anti-tumor therapeutics. Here we review the therapeutic potential of DNMT and HDAC inhibitors as anti-cancer drugs, as evaluated in clinical trials, and their angiostatic activities, apart from their inhibitory effects on tumor cells.