The development of Pythia, a deep learning framework, marks a significant advancement in CRISPR–Cas9 genome engineering. It forecasts optimal repair templates enabling predictable and precise gene editing across diverse cellular contexts, including non-dividing cells. This innovation addresses challenges in gene integration and editing accuracy, facilitating both in vivo and in vitro applications. Published in Nature Biotechnology, Pythia represents a leap forward in achieving reliable and efficient genome modifications crucial for therapeutic and research purposes.