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Biological wastewater treatment plants (BWWTPs) based on the activated sludge (AS) process have dramatically improved worldwide water sanitation despite increased urbanization and industrialization. However, current AS-based operations are considered economically and environmentally unsustainable. In this Perspective, we discuss our current understanding of microbial populations and their metabolic transformations in AS-based BWWTPs in view of developing more sustainable processes in the future. In particular, much has been learned over the course of the past 25 years about specialized microorganisms, which could be more comprehensively leveraged to recover energy and/or nutrients from wastewater streams. To achieve this, we propose a bottom-up design approach, focused around the concept of a wastewater biorefinery column, which would rely on the engineering of distinct ecological niches into a BWWTP in order to guarantee the targeted enrichment of specific organismal groups which in turn will allow the harvest of high-value resources from wastewater. This concept could be seen as a possible grand challenge to microbial ecologists and engineers alike at the centenary of the discovery of the AS process.