Ecoregions, i.e., areas exhibiting relative homogeneity of ecosystems, are units of analysis that are increasingly important in environmental assessment and management. Ecoregions provide a holistic framework for flexible, comparative analysis of complex environmental problems. Ecoregions mapping has intellectual foundations in both geography and ecology. However, a hallmark of ecoregions mapping is that it is a truly interdisciplinary endeavor that demands the integration of knowledge from a multitude of sciences. Geographers emphasize the role of place, scale, and both natural and social elements when delineating and characterizing regions. Ecologists tend to focus on environmental processes with special attention given to energy flows and nutrient cycling. Integration of disparate knowledge from the many key sciences has been one of the great challenges of ecoregions mapping, and may lie at the heart of the lack of consensus on the “optimal” approach and methods to use in such work. Through a review of the principal existing US ecoregion maps, issues that should be addressed in order to advance the state of the art are identified. Research related to needs, methods, data sources, data delivery, and validation is needed. It is also important that the academic system foster education so that there is an infusion of new expertise in ecoregion mapping and use.