Targeted drugs have changed cancer treatment but are often ineffective in the long term against solid tumours, largely because of the activation of heterogeneous oncogenic pathways. A central common signalling mechanism in many of these pathways is proline-directed phosphorylation, which is regulated by many kinases and phosphatases. The structure and function of these phosphorylated proteins are further controlled by a single proline isomerase: PIN1. PIN1 is overactivated in cancers and it promotes cancer and cancer stem cells by disrupting the balance of oncogenes and tumour suppressors. This Review discusses the roles of PIN1 in cancer and the potential of PIN1 inhibitors to restore this balance.