A three tier regional economic indicator framework has been created to address the tran-sition necessary for economic regions moving from a manufacturing-based to a knowledge-based economy. The proposed framework responds to a basic weakness of a knowledge defi-cient region. The framework is consistent with a set of five regional strategies adopted by the leadership of the regional economic initiative. The goal is that the unique set of outcomes of-fered will become a critical part of the distinctive strategies for economic development, as well as a tool to facilitate communication with the legislature and the general public. Early findings based on current use of the framework are reported. The findings illustrate the simplicity and robustness of the framework. The framework is divided into three complementary frames of measures and indicators: the regional framework, the sub-regional framework, and the clusters framework. The framework of indicators uses the system approach of inputs (assets, enablers), processes, and outcomes. The regional framework includes the following aspects: cultural enab-lers, physical and administrative infrastructure, quality of life, education, renovation, human, process, market, and financial capital. The framework also includes the need to assess the cul-tural readiness of the region to adopt the new economy‟s realities. For the indicators to be si-multaneously valid and helpful, they had to identify measurable variables and be operational (i.e., to be affected by the policies and decisions of the driving actors). Where possible, the re-gion was benchmarked against national averages to allow for external observation as a mea-ningful comparison. Where the national average was not available, the region was ben-chmarked against the state (Wisconsin). Sub-regions were also identified to provide depth to the regional indicators. The rationale for this proposal is that in a large and diverse region (e.g., the 18 counties in the Northeast Wisconsin (NEW) region that is a mix of rural and urban communities with very diverse demographics), there are specific sub-regional idiosyncrasies. In the case of the Northeast Wisconsin region, four sub-regions were identified. It was also clear that by monitoring the major industrial clusters, the unique aspects that are more appropriately measured at the cluster level of analysis might be captured. Twelve major clusters were identified.