Abstract The basic science and preclinical studies of intellectual and developmental disabilities (IDDs) have outpaced the development and validation of tools to measure treatment response in human clinical trials. While an ever-increasing number of targeted treatments documented to normalize neurobiological and behavioral phenotypes in animal models are advanced for experimental evaluation in humans with IDDs, limitations of outcome measures and lack of consensus among investigators have been major barriers to progress in the translational pipeline. In fact, it has been argued that true benefits of experimental treatments have been missed in some so-called “failed trials” due to lack of sensitivity to change in the outcome measures for the disorder of interest, and/or susceptibility to large placebo effects that obscure these potentially real changes. For the past 5 years we have made substantial progress validating the National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) for use as a set of outcome measures for individuals with IDDs and have generated solid psychometric evidence of its utility for a high proportion of individuals with mental ages at or above 5 years. Despite these important advances, our work has also highlighted critical knowledge gaps, and potential solutions. First, some of the established NIHTB-CB tests were not feasible or lacked acceptable psychometric properties for more severely affected or very young individuals with IDD – subgroups that remain critical targets for intervention – and the battery does not cover important domains which can be measured very early in development. Second, while cross- sectional data is available from the battery’s normative sample, longitudinal trajectories of NIHTB-CB test scores among people with IDD are not available. And third, despite evidence of sensitivity to developmental changes, there are currently no data to demonstrate that the NIHTB-CB is sensitive to treatment-related change. For the current project we will a) optimize the NIHTB-CB for lower functioning individuals with moderate and severe IDD, b) complete development and validation of new NIHTB-CB tests to fill critical gaps in cognitive constructs not currently assessed, including Concept Formation and Numeracy, c) extend understanding of developmental changes in the NIHTB- CB tests using expanded longitudinal observations in children and youth with IDD, and d) examine the preliminary sensitivity of the NIHTB-CB to detect treatment-related cognitive changes utilizing a randomized, double-blind placebo-controlled stimulant (methylphenidate extended release liquid) trial in children and adolescents with IDD + ADHD. It is anticipated that successful fulfillment of these knowledge gaps will result in a scalable and standardized cognitive battery suitable for widespread use in the field and consideration for FDA registration.