In a new study, researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig addressed a long-standing challenge in CRISPR genome editing: how to accurately predict guide RNA (gRNA) activity. Their breakthrough to robustly predict synthetic gRNA activity came from a key observation - chemically synthesized gRNAs are far less affected by target sequence features than gRNAs transcribed from DNA templates, allowing for more reliable and generalizable predictions.