Aberrant regulation of the Wnt signalling pathway has emerged as a prevalent theme in cancer biology. This chapter summarizes the research that provides a proof of concept for inhibiting Wnt signalling in cancer, the potential means by which this could be achieved, and some recent advances towards this goal. A brief discussion of molecular diagnostics and possible safety concerns is also provided. The EMBO Journal (2012) 31, 2737-2746. doi:10.1038/emboj.2012.126; Published online 22 May 2012