Global mental health is a critical issue, with mental, neurological and substance-use (MNS) disorders accounting for 13% of the global disease burden, surpassing cardiovascular disease and cancer. These disorders include schizophrenia, depression, epilepsy, dementia, and alcohol dependence, which contribute significantly to the global disease burden. The absence of cures and preventive interventions reflects a limited understanding of the brain and its mechanisms. Effective treatments are often not available to those in greatest need, and there is an unequal distribution of mental health professionals globally. The Grand Challenges in Global Mental Health initiative has identified research priorities for the next 10 years to improve the lives of people with MNS disorders. The initiative, funded by the US National Institute of Mental Health (NIMH) and supported by the Global Alliance for Chronic Diseases (GACD), aims to address the lack of investment in research and treatment for these disorders. The initiative emphasizes the need for global cooperation in research, data sharing, and capacity-building. It also highlights the importance of addressing the needs of children, as many mental disorders involve developmental processes. The initiative identifies 25 grand challenges, including the need for a life-course approach to research, the importance of mental capital, and the need for systems interventions to improve health services. The challenges also emphasize the need for evidence-based interventions and the relationship between environmental exposures and MNS disorders. The top five challenges, ranked by disease burden reduction, impact on equity, immediacy of impact, and feasibility, should serve as a starting point for immediate research and policy prioritization. The initiative calls for long-term investment and collaboration among researchers, funders, and policymakers to address the challenges in global mental health. The goal is to reduce the burden of MNS disorders and improve the quality of life for affected individuals. The initiative highlights the importance of addressing the needs of people with MNS disorders in the context of economic and social development.Global mental health is a critical issue, with mental, neurological and substance-use (MNS) disorders accounting for 13% of the global disease burden, surpassing cardiovascular disease and cancer. These disorders include schizophrenia, depression, epilepsy, dementia, and alcohol dependence, which contribute significantly to the global disease burden. The absence of cures and preventive interventions reflects a limited understanding of the brain and its mechanisms. Effective treatments are often not available to those in greatest need, and there is an unequal distribution of mental health professionals globally. The Grand Challenges in Global Mental Health initiative has identified research priorities for the next 10 years to improve the lives of people with MNS disorders. The initiative, funded by the US National Institute of Mental Health (NIMH) and supported by the Global Alliance for Chronic Diseases (GACD), aims to address the lack of investment in research and treatment for these disorders. The initiative emphasizes the need for global cooperation in research, data sharing, and capacity-building. It also highlights the importance of addressing the needs of children, as many mental disorders involve developmental processes. The initiative identifies 25 grand challenges, including the need for a life-course approach to research, the importance of mental capital, and the need for systems interventions to improve health services. The challenges also emphasize the need for evidence-based interventions and the relationship between environmental exposures and MNS disorders. The top five challenges, ranked by disease burden reduction, impact on equity, immediacy of impact, and feasibility, should serve as a starting point for immediate research and policy prioritization. The initiative calls for long-term investment and collaboration among researchers, funders, and policymakers to address the challenges in global mental health. The goal is to reduce the burden of MNS disorders and improve the quality of life for affected individuals. The initiative highlights the importance of addressing the needs of people with MNS disorders in the context of economic and social development.