To identify genes for which essentiality is dependent on the genetic background, Chen et al. used a library of 80 Saccharomyces cerevisiae strains, each of which represses an essential gene following doxycycline treatment. After exposing 60 million cells of each strain to doxycycline, they used genome sequencing on the rare surviving cells to identify naturally occurring mutations that rescued the lethality of the repressed essential gene. Overall, 17 gene pairs were identified across 5 conditionally essential genes. The lethal effects of the loss of ADE13 — which encodes adenylosuccinate lyase (ADSL), mutations of which cause the human metabolic disorder ADSL deficiency — could be rescued by mutations in five different genes. In Caenorhabditis elegans, knockdown of one of these genes (phosphoribosylaminoimidazole carboxylase) substantially reduced the pathological effects of ADSL knockdown. Such strategies might enable human therapeutics, by targeting the genetic interactions contributing to pathology rather than attempting functional replacement of a primary genetic defect.