Epigenetic programs are now widely recognized as being critical to the biological processes of cancer genesis. However, it has not been comprehensively understood how and to what degree they can influence anticancer drugs responses. The development of drugs targeting epigenetic regulation has generated great enthusiasm, with a growing number in clinical development. We highlight here that epigenetic modifications can be involved in the regulation of genes responsible for the absorption, distribution, metabolism and excretion of drugs and for the pathological progression of cancer, thereby affecting anticancer drug responses. The major epigenetic regulatory mechanisms are reviewed, including DNA methylation, miRNA regulation and histone modification, with the aim of promoting rational use of anticancer drugs in the clinic and epigenetic drug development.