Kim et al. reveal why loss of the p53 tumour suppressor protein correlates with the activation of WNT signalling in cancer. During WNT signalling, WNT stabilizes β-catenin, which forms a complex with T cell factor and lymphoid enhancer factor (TCF/LEF)-family transcription factors. Here, the authors found that p53, as well as the microRNA miR-34 family, which are transcriptional targets of p53, inhibited WNT signalling. Genes in the WNT pathway, including the genes encoding WNT1 and β-catenin, were identified as direct miR-34 targets, and knockdown of p53 reduced miR-34 levels and increased WNT signalling output. Furthermore, analysis of breast cancer samples showed that genes predicted to be increased when miR-34 activity is low correlated with signatures of high β-catenin–TCF/LEF activity and mutant p53. Thus, p53 negatively regulates WNT signalling through miR-34. This helps to explain why WNT signalling is activated in tumours lacking functional p53.