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Abstract Genetic Programming (GP) often uses large training sets and requires all individuals to be evaluated on all training cases during selection. Random down-sampled lexicase selection evaluates individuals on only a random subset of the training cases, allowing for more individuals to be explored with the same number of program executions. However, sampling randomly can exclude important cases from the down-sample for a number of generations, while cases that measure the same behavior (synonymous cases) may be overused. In this work, we introduce Informed Down-Sampled Lexicase Selection. This method leverages population statistics to build down-samples that contain more distinct and therefore informative training cases. Through an empirical investigation across two different GP systems (PushGP and Grammar-Guided GP), we find that informed down-sampling significantly outperforms random down-sampling on a set of contemporary program synthesis benchmark problems. Through an analysis of the created down-samples, we find that important training cases are included in the down-sample consistently across independent evolutionary runs and systems. We hypothesize that this improvement can be attributed to the ability of Informed Down-Sampled Lexicase Selection to maintain more specialist individuals over the course of evolution, while still benefiting from reduced per-evaluation costs.