The development of improved treatments and greater understanding of existing interventions will address the enormous public health burden resulting from limited efficacy and safety of existing pain treatments, increasing prevalence of opioid and stimulant addiction, safety risks of adult anesthesia (e.g., post-operative delirium), and potential developmental neurotoxicities associated with pediatric anesthesia, especially in vulnerable children. A compelling rationale for developing new paradigms to identify treatments with improved efficacy and safety is provided by the limitations of existing approaches to identifying novel treatments, inadequate understanding of the explanations for negative and inconclusive clinical trials, incomplete characterizations of treatment risks, and lack of knowledge of factors associated with clinical trial assay sensitivity. The mission of the public-private partnership described in this application will be to “identify, prioritize, sponsor, coordinate, and promote innovative activities — focusing on maximizing treatment benefits and minimizing their risks — that will expedite the discovery and development of improved analgesic, addiction, and adult and pediatric anesthetic treatments for the benefit of the public health.” The major objective of the partnership will be to provide a multidisciplinary collaborative framework to prioritize research objectives and conduct methodologically-focused studies and other activities to facilitate the discovery and development of analgesic, addiction, and anesthetic interventions with greater efficacy and safety. In each of these therapeutic areas, there are multiple opportunities to develop innovative research methods that can accelerate the translation of preclinical research results to phase 2 and 3 clinical trials and to meaningful studies of real-world data and evidence. Systematic efforts to increase the efficiency and informativeness of clinical trials and other types of clinical research to detect efficacy and effectiveness, determine patient preferences, and improve assessments of safety — for example, by analyzing the methods and results of preclinical studies, randomized clinical trials, and rigorous observational studies — can provide the foundation for evidence-based recommendations for the design and interpretation of future research. To achieve its objectives, the partnership will include representatives from academia, multiple professional societies, government agencies, patient advocacy organizations, and industry. The overarching goals and promise of the public-private partnership are to improve the lives of patients of all ages and thereby contribute meaningful benefits to the public health.