The methyl-CpG-binding domain (MBD) proteins 'read' and interpret the methylation moieties on DNA, and thus are critical mediators of many epigenetic processes. Currently, the MBD family comprises five members; MBD1, MBD2, MBD3, MBD4 and MeCP2. Although not a 'classical' MBD protein, Kaiso also mediates transcriptional repression by using zinc finger domains to bind its targets. Since DNA hypermethylation is a well-recognized mechanism underlying gene silencing events in both tumorigenesis and drug resistance, it is likely that the MBD proteins may be important modulators of tumorigenesis. We review the recent work addressing this possibility, and discuss several of the MBD proteins as potentially excellent novel therapeutic targets.