Editor’s summary To date, our ability to functionally interrogate the consequences of structural variation in the human genome has been stymied by our inability to efficiently engineer one or many structural variants to study. Koeppel et al. and Pinglay et al. developed SCRaMbLE and Genome-Shuffle-seq, respectively, enabling the multiplex generation of thousands of structural variants in human and mouse genomes in a single experiment (see the Perspective by Seczynska and Steinmetz).