RxStat uses existing datasets to generate information that can be used to tailor targeted interventions and policy responses in reducing deaths and illness from prescription opioid and other drug misuse. This manual is a resource and guide for creating similar initiatives in other U.S. cities and counties. New York's RxStat initiative was established in 2012. It relies on the collaboration of public health and public safety agencies in a jurisdiction. RxStat incorporates data from local, State, and Federal government sources and applies a public health analysis for comparing and triangulating findings across datasets. This effort requires investing in data analysts to conduct the work and a willingness among public health and public safety agencies to share relevant data for analysis. Section one of this manual identifies and describes key elements in the five stages of RxStat development, which are 1) basics, 2) getting started, 3) building content, 4) managing process, and 5) moving forward. This section includes suggestions for structuring the work, as well as observations and examples from the experiences with RxStat in New York City in its first 2 years. A checklist for RxStat implementation is presented at the end of the section. Section Two describes each of the datasets that have proven useful in New York's initiative, as well as guidance for accessing, preparing, and analyzing similar datasets available in other jurisdictions. Because RxStat relies on standard administrative datasets, it can be replicated in other jurisdictions.