Advances in genetics have made it feasible to genetically engineerinsect strains carrying a conditional lethal trait on multiple loci. Wemodel the release into a target pest population of insects carrying adominant and fully penetrant conditional lethal trait on 1–20 loci.Delaying the lethality for several generations after release allows thetrait to become widely spread in the target population before beingactivated. To determine effectiveness and optimal strategies for suchreleases, we vary release size, number of generations until theconditional lethality, nonconditional fitness cost resulting from geneinsertions, and fitness reduction associated with laboratory rearing.We show that conditional lethal releases are potentially orders ofmagnitude more effective than sterile male releases of equal size, andthat far smaller release sizes may be required for this approach thannecessary with sterile males. For example, a release of male insectscarrying a conditional lethal allele that is activated in theF₄ generation on 10 loci reduces the target population to10⁻⁴ of no-release size if there are initially tworeleased males for every wild male. We show how the effectiveness ofconditional lethal releases decreases as the nonconditional fitnessreduction (i.e., fitness reduction before the trait becomes lethal)associated with the conditional lethal genes increases. For example, ifthere is a 5% nonconditional fitness cost per conditional lethalallele, then a 2:1 (released male:wild male) release with conditionallethal alleles that are activated in the F₄ generationreduces the population to 2–5% (depending on the degree of densitydependence) of the no-release size. If there is a per-allele reductionin fitness, then as the number of loci is increased there is atrade-off between the fraction of offspring carrying at least oneconditional lethal allele and the fitness of the released insects. Wecalculate the optimal number of loci on which to insert the conditionallethal gene given various conditions. In addition, we show howlaboratory-rearing fitness costs, density-dependence, and all-maleversus male-female releases affect the efficiency of conditional lethalreleases.