Abstract: The disclosure provides compositions and methods for high-efficiency genome editing in mammals. In some aspects, the disclosure provides guide RNA-retron cassettes, RNA-guided nuclease (e.g., Cas9)-reverse transcriptase fusion protein encoding cassettes, and vectors comprising the cassettes. Also provided are mammalian host cells that have been transfected with the vectors. In other aspects, guide-retron donor DNA molecules are provided. In some other aspects, methods for genome editing in mammals and the screening of genetic loci are provided. In further aspects, methods and compositions are provided for the prevention or treatment of genetic diseases and for other applications. Kits for genome editing and screening are also provided.