Modulating protein-protein interactions constitutes a promising strategy both for the investigation of biological mechanisms and for developing new therapeutic approaches. Among the many types of inter-actions, PDZ domain-mediated interactions (PDMIs) have emerged over the last decade as attractive targets in the drug discovery field. Indeed, these small domains are involved in the regulation of many signaling pathways and possess structural properties which are favorable for the design of competing ligands. Herein, we describe the recent approaches developed to inhibit this class of protein-protein interactions.