To benefit from the predicted superior properties of high-entropy alloy (HEA) nanostructures in future energy solutions, many fundamental scientific questions and challenges still remain. These include: the development of new synthetic routes to achieve nanostructures with compositional, morphological and structural control; development of new high-throughput characterization routines to examine the structural and elemental distribution of multi-elemental nanostructured materials with high spatial resolution; the development of theoretical models to predict the catalytic properties and active sites driving the reactions on multi-elemental surfaces; the evolution of HEA nanostructured catalysts under realistic operating conditions; magnetic properties of HEAs. This Faraday Discussion aims to bring together pioneers within this area in a cross-disciplinary manner by providing a platform to explore possible solutions to these challenges, while establishing a fundamental understanding of these novel materials.