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Internal variability in the climate system confounds assessment of human-induced climate change and imposes irreducible limits on the accuracy of climate change projections, especially at regional and decadal scales. A new collection of initial-condition large ensembles (LEs) generated with seven Earth system models under historical and future radiative forcing scenarios provides new insights into uncertainties due to internal variability versus model differences. These data enhance the assessment of climate change risks, including extreme events, and offer a powerful testbed for new methodologies aimed at separating forced signals from internal variability in the observational record. Opportunities and challenges confronting the design and dissemination of future LEs, including increased spatial resolution and model complexity alongside emerging Earth system applications, are discussed.