The ability to install large DNA sequences into specified locations in the human genome has far-reaching implications, including paving the way for single-drug treatments of mutationally diverse loss-of-function genetic diseases. CRISPR-associated transposases (CASTs) are naturally occurring systems that support RNA-programmable insertion of gene-sized DNA but have shown minimal activity in human cells. Witte et al. developed a continuous evolution platform to improve CAST activity, yielding an evolved CAST with more than 200-fold increased activity in human cells. This enzyme enables efficient gene integration across a variety of therapeutically relevant genomic sites in multiple human cell types, representing a versatile new platform for mammalian cell genome editing. —Di Jiang