Highlights • Chemokines comprise discrete structural regions that mediate antimicrobial activity. • Bacterial elements besides the membrane are targets of antimicrobial chemokines. • CXCL10 kills bacterial pathogens using at least two distinct mechanisms. • Chemokines exert antimicrobial and immunomodulatory effects of therapeutic interest. • Chemokine-derived peptides merit investigation as a novel therapeutic strategy. Abstract Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens. [ABSTRACT FROM AUTHOR]