Genome editing is facilitating the manipulation of genomes on an unprecedented scale. It promises to revolutionize our ability to study gene function and generate models of human genetic disease in a range of organisms, most notably in mammals such as the mouse. Is this new technology likely to be disruptive to our research practices in any way? Will it alter the ways in which we implement the ethical imperatives of the 3Rs? In short, what ethical questions are raised by genome editing of mammals in a biomedical research context?