The growing evidence that a number of genes are epigenetically silenced by methylation in normal tissues (reviewed in Strathdee et al, 2004) and that some of these genes such as S100A4 may be tumour promoting, now forces a reconsideration of our understanding of how alterations in the epigenome contribute to cancer development, and the rationale and mechanisms underlying the therapeutic efficacy of such ‘epigenetic’ therapies. Here, S100A4 is linked to cancer.