The discovery of the natural product nodulisporic acid A (NsA A) and its potent, systemic insecticidal activity at Merck Research Laboratories in 1992 stimulated intense scientific scrutiny. Interest in this new class of indole diterpenes led to extensive delineation of its properties, both chemical and biological. Synthetic modification of NsA A served to identify its pharmacologically permissive and nonpermissive regions, produced semisynthetic derivatives with enhanced adulticidal flea efficacy (both in vitro and in vivo), and provided useful tools to support biological studies. Early observations in rodent models showed a wide therapeutic index for NsA A and detailed mechanism of action investigations demonstrated that it selectively modulated an invertebrate specific glutamate-gated ion channel for which no mammalian homolog exists. Consistent with these mechanistic conclusions, dogs treated orally with either NsA A or closely related amide analogs (15 mg / kg dosages) showed no apparent toxicity, and measurement of systemic flea efficacy in these animals demonstrated that prolonged antiparasitic activity was attained, up to 14 days subsequent to treatment with a single p.o. dose for fleas or up to 4 weeks for ticks. The extended flea efficacy was correlated to both the in vivo pharmacokinetic profile of a given analog and its intrinsic in vitro potency against fleas. In addition, studies directed towards the total synthesis of NsA A have been reported.