Plague, caused by Yersinia pestis, is a widespread threat to endangered black-footed ferrets (Mustela nigripes) and their primary prey, prairie dogs (Cynomys spp.). Wildlife biologists most commonly manage plague using insecticides to control fleas, the primary vectors of Y. pestis. We tested edible baits containing the insecticides lufenuron and/or nitenpyram in prairie dogs. During a laboratory study, we treated 26 white-tailed prairie dogs (Cynomys leucurus) with lufenuron at 300 mg/kg body mass. All animals remained clinically healthy over the 9 wk monitoring period. Although serum lufenuron concentrations were >130 ppb in two treatment groups at week 1, concentrations declined to ≤60 ppb after 3 wk in non-torpid prairie dogs and after 7 wk in torpid prairie dogs. In a field experiment, we tested baits containing a combination of 75 mg lufenuron and 6 mg nitenpyram, respectively, in black-tailed prairie dogs (Cynomys ludovicianus). We uniformly distributed baits at 125 baits/ha on two plots (treated once) and 250 baits/ha on two plots (each treated twice 4.4 wk apart). Following treatments, flea abundance increased on prairie dogs and remained stable in burrows. Our findings indicate that baits containing lufenuron and nitenpyram, at the reported treatment rates, are ineffective tools for flea control on prairie dogs. Future experiments might evaluate efficacy of higher doses of lufenuron and nitenpyram, and repetitive treatments at differing intervals over time to evaluate potentially therapeutic treatments.