Water scarcity is one of the greatest global crises of our time. Increasing water supply beyond what is available from the hydrological cycle can be achieved by seawater desalination and wastewater reuse. Highly effective, low-cost, robust membrane-based technologies for desalination and wastewater reuse are needed, with minimal impact on the environment. However, progress in current state-of-the-art water purification membranes has been limited. This presentation will critically discuss and evaluate recent research efforts in the past 15 years to (i) lower energy consumption for water desalination by improving membrane water permeability, (ii) reduce the cost of water desalination via increased water-salt selectivity, and (iii) enhance membrane ion selectivity for applications at the water-energy nexus. The presentation will highlight the emerging area of ion selectivity where high precision ion separation is desired. We will discuss how insights from nanofluidics and ion-selective biological channels establish the basis for a new class of membranes with ion-ion selectivity. A few examples will be provided to elucidate the mechanisms of ion transport and selectivity in membranes with sub-nanometer pores. The presentation will conclude with a discussion on research directions and critical challenges for developing ion-selective membranes.