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Antimicrobial resistance (AMR) disproportionately affects people who are immunocompromised due to their frequent encounters with the health-care system and repeated, prolonged exposure to antibiotics. AMR threatens to undermine continued advances in cancer care, haematopoietic cell transplantation, and solid organ transplantation by severely restricting therapeutic options. The convergence of several factors in the diagnostic evaluation of infection among individuals with immunocompromising conditions contributes to excess and inappropriate antibiotic use. Diagnostic and antimicrobial stewardship are key complementary strategies to address these challenges with shared goals of improving patient outcomes, reducing harm, and mitigating the risk of AMR. In this Series paper, we discuss opportunities to enhance use of existing diagnostic tools (eg, culture-based diagnostics, molecular diagnostics, and other tools such as antibiotic allergy delabelling), emerging diagnostic tools (eg, metagenomic sequencing and host response profiling), and digital innovation, to optimise antibiotic use, and the potential for precision medicine approaches to combat AMR in people who are immunocompromised.