Regional scientists have long faced challenges in developing the interdisciplinary field where their focus is on the spatial context of social, economic and environmental phenomena, and dealing with spatial data presents considerable methodological challenges. This article discusses the evolution of Regional Science, the critiques it has received and the challenges it has confronted. It addresses specifically some contemporary challenges that relate to methodological issues, such as: how to measure and model endogenous regional growth performance; the limitations of using de jure regions rather than functional regions as the spatial framework in regional analysis; the need to making greater use of unit record data and integrating those data into generalised spatial frameworks; and making use of the opportunities offered by «big data» in urban and regional analysis.Regional scientists have long faced challenges in developing the interdisciplinary field where their focus is on the spatial context of social, economic and environmental phenomena, and dealing with spatial data presents considerable methodological challenges. This article discusses the evolution of Regional Science, the critiques it has received and the challenges it has confronted. It addresses specifically some contemporary challenges that relate to methodological issues, such as: how to measure and model endogenous regional growth performance; the limitations of using de jure regions rather than functional regions as the spatial framework in regional analysis; the need to making greater use of unit record data and integrating those data into generalised spatial frameworks; and making use of the opportunities offered by «big data» in urban and regional analysis.