Epigenetic inactivation of tumour suppressor genes, in contrast to gene mutations, can be modulated or reversed by small molecules. This has lead to several recent studies of drugs targeting epigenetic mechanisms as novel cancer therapies. So far, epigenetic therapies, including HDAC inhibitors and demethylating agents, show considerable activity in haematological malignancies, but their value in the treatment of solid tumours remains much more uncertain. This review will discuss some of the challenges that are expected in the treatment of solid tumours with epigenetic therapies and discuss approaches to overcome these obstacles. There is an increasing need for trials driven by pharmacodynamic biomarkers for these agents, which are aimed at finding the optimum biological dose rather than the maximal-tolerated dose, and also investigating their use in combination with cytotoxics--for example as chemosensitisers. Such trials already suggest that improved tumour delivery and specificity, with decreased normal tissue toxicity, will be required to take full advantage of this class of agents in solid tumours.