Negative cross-resistance (NCR) occurs when a mutant allele confers (i) resistance to one toxic chemical and (ii) hyper-susceptibility to another. Sequential deployment of NCR toxins is useful for insect control in few situations (Pittendrigh et al., 2000). Using Monte Carlo simulations, we investigated the concurrent use of a pair of NCR toxins to control a hypothetical insect pest population. When the toxins killed more heterozygotes than homozygotes, the resistance allele became either extremely common or rare depending on starting allelic frequency. If the NCR toxins did not kill the two homozygous groups equally, then the toxin with lesser toxicity eventually played a greater role in the control of the pest population. Based on our results, we present an approach for the systematic development of an NCR toxin after the commercial release of the first toxin. First, large-scale screens are performed to find chemicals that kill the resistant homozygous insects, but not the susceptible ones. Chemicals that preferentially kill resistant insects are then tested for toxicity to the heterozygotes. Those highly toxic to both homo- and heterozygotes are given the highest priority for development. This screen can be adapted to identify compounds useful in controlling antibiotic-, herbicide- or fungicide-resistant organisms.