Antimicrobial resistance (AMR) is a major global public health challenge. It is driven by inappropriate antimicrobial use and inadequate infection prevention and control across human, animal, plant, and environmental health settings. With resistance to second and third-line antimicrobials growing the threat is profound. Key messages for policy-makers are that: National and international commitments to a “One-Health” approach offer some hope and bring sectors, disciplines, and communities together but despite years of policy discussion and much agreement, action has often been sluggish and ineffective. The factors that enable it work best in combination and include: –. Strong leadership commitment at all levels. –. Clear roles, responsibilities, and accountability mechanisms. –. Monitoring and surveillance with rapid feedback. –. Multidisciplinary teams and training. –. Tailored targets and benchmarking at multiple levels. –. Reimbursement models that incentivise appropriate antimicrobial use and prevention. –. Educational programmes and the promotion of awareness. –. Adequate funding for research, and –. Policies which support sustainable innovation and access to effective antibiotics. There are key, evidence-informed interventions that countries can usefully implement: 1. In human health settings, key measures that work include: –. Antimicrobial stewardship programmes. –. Clinical decision support systems (CDSS) for prescribers. –. Control of falsified and counterfeit antimicrobials. –. Infection prevention and control. –. Vaccination to prevent the emergence and spread of key pathogens. 2. Key effective interventions in animal health settings include: –. Regulation and supervision to promote prudent use of antimicrobials. –. Improved biosecurity. –. Vaccination to prevent emergence and spread of key pathogens. –. Food safety compliance programmes. 3. Key steps that can make a difference in environmental health settings include: –. Improving wastewater treatment facilities. –. Limiting concentration of antimicrobials in discharges from the pharmaceutical industry. –. Improving waste management in agricultural production: including an absence of accountability mechanisms, healthcare and veterinarian staffing shortages, limited diagnostic and surveillance capacity, delayed feedback of surveillance data, misinformation on social media, shortages of essential antimicrobials and vaccines and lack of resources. from legislation, to surveillance, to technical advice. The EU adds particular value in evidence-based guidelines; the efficacy and safety of antimicrobials and vaccines; joint procurement; research funding; and in providing platforms to coordinate policy and share good practices. including in strengthening AMR national action plans to achieve EU-level targets. Strong leadership, balancing top-down and bottom-up interventions, optimizing the use of public resources and fostering accountability and responsiveness all support implementation at the national (and sub-national) level. mechanisms at the European and global levels to foster effective links across sectors and between European, national, regional and local stakeholders. , and countries holding the Presidency of the Council of the EU can play a pivotal role in advancing this agenda.