The threat of antimicrobial resistance has global health and economic consequences. Medical strategies to reduce unnecessary antibiotic prescribing, to conserve the effectiveness of current antimicrobials in the long term, inevitably result in short-term costs to health care providers. Economic evaluations of health care interventions therefore need to consider the short-term costs of interventions, to gain future benefits. This represents a challenge for health economists, not only in terms of the most appropriate methods for evaluation, but also in attributing the potential budget impact over time and considering health impacts on future populations. This commentary discusses the challenge of accurately capturing the cost-effectiveness of health care interventions aimed at tackling antimicrobial resistance. We reflect on methods to capture and incorporate the costs and health outcomes associated with antimicrobial resistance, the appropriateness of the quality-adjusted-life year (QALY), individual time preferences, and perspectives in economic evaluation.