Quorum sensing is a microbial signaling process that relies on the production, release, and response to extracellular signaling molecules called autoinducers. This Review covers quorum‐sensing systems controlled by a pyrazine‐type autoinducer, 3,5‐dimethyl‐pyrazin‐2‐ol (DPO). The systems we cover span the human pathogen Vibrio cholerae, where DPO regulates pathogenicity and biofilm formation, and phage VP882, where DPO controls lytic development and viral dissemination. In both cases, detection of DPO occurs via a dedicated receptor‐transcription factor called VqmA. In V. cholerae, DPO activates the production of the VqmR regulatory RNA, and in the phage, DPO triggers production of the small protein Qtip. We present our current understanding of DPO biosynthesis, ongoing efforts to resolve the mechanisms underlying DPO‐mediated signal transduction, and a forward‐facing perspective on the role of DPO in human health and undiscovered pyrazine‐based signals in biology, more broadly.