Tumour suppressor genes in cancer cells are frequently silenced by promoter CpG methylation, which has led to the pursuit of DNA methylation inhibitors as potential cancer therapeutics to reactivate these genes. However, DNA methylation in gene bodies is associated with the opposite effect (that is, gene activation). Yang et al. carried out a genome-scale analysis of DNA methylation and gene expression changes in colon cancer cells in response to treatment with DNA methylation inhibitors. Treatment led to widespread gene-body demethylation and transcriptional downregulation. Furthermore, many of the genes affected were overexpressed in colon cancer tissue samples and were regulated by the MYC oncoprotein. Thus, antiproliferative effects of DNA methylation inhibitors are likely to be mediated, in part, through the downregulation of overexpressed oncogenes.