The Eastern Mediterranean Region is challenged by growing epidemics of HIV/AIDS, viral hepatitis and sexually transmitted infections (STIs). Although some progress has been made in all three disease areas, the regional response is off-track and most of the 2020 regional targets were not achieved. The HIV/AIDS epidemic is growing faster than the response, with increases in incidence and mortality over the past decade. Similarly, despite progress in hepatitis B third-dose coverage and in testing and treatment for hepatitis C virus, the coverage of other key interventions – including birth-dose vaccination, injection safety, harm reduction, and testing and treatment – is still low. STIs are increasing in the Region, with a limited response that does not match the burden of disease. Furthermore, COVID-19 disrupted services, exposing profound weaknesses in our health systems and their lack of resilience in emergencies. Overall, achieving Sustainable Development Goal 3 and the global targets on HIV, viral hepatitis and STIs by 2030 will be difficult if the Region continues at the current pace. Only a focus and surge of efforts will enable the Region to meet the global targets for the three disease areas by 2030.