Muscarinic acetylcholine receptors (mAChRs) are G-protein-coupled receptors that are underutilized for controlling insect pests despite their involvement in various physiological functions. To-date, there are no commercialized insecticides targeting insect mAChRs. In this dissertation, effective target-site synergism was demonstrated in susceptible Drosophila melanogaster where mAChR agonism by pilocarpine enhanced the toxicity of insecticides targeting gamma-aminobutyric acid (GABA)-gated chloride channels, indicating the potential of insect mAChRs as a target for developing novel insecticides/synergists to control resistant pests. A point mutation (A301S) in the GABA-gated chloride channel confers resistance to dieldrin (Rdl), lindane, and fipronil, which I have confirmed using different routes of exposure. However, the same synergistic effect was not achieved in the resistant strain with the presence of this target-site mutation. This difference between two strains is perplexing because there is a change in the efficacy of several compound classes that do not directly act upon GABA-gated chloride channels. Specifically, a point mutation appears to influence how the insect central nervous system (CNS) responds to muscarinic compounds, type I pyrethroids, and acetylcholinesterase (AChE) inhibitors. In the case of acetylcholinesterase, the resistant insect increases the expression of Ace gene encoding this enzyme. Fully understanding how the CNS responds to receptor modifications is not well understood and could have a significant impact to pest management strategies. / Doctor of Philosophy / Insects significantly influence the food production, health, and the economy of the human world. Control of insect pest outbreaks relies on the proper use of insecticides. However, extensive application of insecticides has resulted in pests being able to adapt to these compounds, through insecticide resistance. Ultimately, this will affect currently used pest management strategies. To help alleviate this urgent problem, my dissertation provided an alternative strategy to control pests, which is to use a mixture of two molecules that influence different targets in the insect nervous system that could reduce the use of toxic or deleterious compounds that are the active ingredients. It is important to not solely rely on current insecticides on the market and find new insecticides that work differently. I used the fruit fly to help me understand how insecticide mixtures would work, but also understand how the complex nature of insect adaptations at the level of the nervous system continues to threaten pest management. Based on studies that were performed here, we now have a better understanding on how to investigate the failure of insecticides in the field, which will ultimately help us make new molecules.