Disclosed are methods and compositions for genetic modification, for example for the treatment of a disease or for production of genetically modified plants. In one aspect, described herein is a method of modifying an endogenous gene in a cell, the method comprising administering to the cell a first nucleic acid molecule comprising a single guide RNA that recognizes a target site in the endogenous gene and a second nucleic acid molecule that encodes a functional domain, wherein the functional domain associates with the single guide RNA on the target site, thereby modifying the endogenous gene.