Nature Biotechnology published multiple advances to expand precise genome engineering using retargeted serine-based enzymes. One report describes retargeted serine integrases designed to streamline genomic integration of DNA, while another introduces an approach using the large serine recombinase Bxb1 for precise insertion of large DNA payloads at desired loci. A third publication outlines “experiment-guided” improvements to predictive modeling of protein ensembles relevant to structure-based engineering. For biotech pipelines, retargeted large-payload systems are a practical route to insert therapeutic genes with less complexity than older multi-step strategies, provided specificity and manufacturability hold up in translational settings.