The research agenda for global mental health and substance-use disorders has been largely driven by the exigencies of high health burdens and associated unmet needs in low- and middle-income countries. Implementation research focused on context-driven adaptation and innovation in service delivery has begun to yield promising results that are improving the quality of, and access to, care in low-resource settings. Importantly, these efforts have also resulted in the development and augmentation of local, in-country research capacities. Given the complex interplay between mental health and substance-use disorders, medical conditions, and biological and social vulnerabilities, a revitalized research agenda must encompass both local variation and global commonalities in the impact of adversities, multi-morbidities and their consequences across the life course. We recommend priorities for research - as well as guiding principles for context-driven, intersectoral, integrative approaches - that will advance knowledge and answer the most pressing local and global mental health questions and needs, while also promoting a health equity agenda and extending the quality, reach and impact of scientific enquiry.