The article discusses the Grand Challenges in Global Mental Health initiative, which aims to address the global burden of mental, neurological, and substance-use (MNS) disorders. These disorders, including schizophrenia, depression, epilepsy, dementia, and alcohol dependence, account for 13% of the global disease burden, surpassing cardiovascular disease and cancer. The initiative, funded by the US National Institute of Mental Health (NIMH) and supported by the Global Alliance for Chronic Diseases (GACD), identifies research priorities for the next 10 years to improve the lives of people with MNS disorders. The prioritization process involved a large international Delphi panel, resulting in 25 grand challenges that emphasize the need for global cooperation, a life-course approach, and evidence-based interventions. The challenges cover a wide range of areas, from preclinical research to policy implementation, and highlight the importance of addressing environmental and sociocultural factors. The article calls for immediate action and long-term investment to achieve significant economic and quality-of-life benefits, despite the challenges in eliminating MNS disorders within the next decade.The article discusses the Grand Challenges in Global Mental Health initiative, which aims to address the global burden of mental, neurological, and substance-use (MNS) disorders. These disorders, including schizophrenia, depression, epilepsy, dementia, and alcohol dependence, account for 13% of the global disease burden, surpassing cardiovascular disease and cancer. The initiative, funded by the US National Institute of Mental Health (NIMH) and supported by the Global Alliance for Chronic Diseases (GACD), identifies research priorities for the next 10 years to improve the lives of people with MNS disorders. The prioritization process involved a large international Delphi panel, resulting in 25 grand challenges that emphasize the need for global cooperation, a life-course approach, and evidence-based interventions. The challenges cover a wide range of areas, from preclinical research to policy implementation, and highlight the importance of addressing environmental and sociocultural factors. The article calls for immediate action and long-term investment to achieve significant economic and quality-of-life benefits, despite the challenges in eliminating MNS disorders within the next decade.