The chapter discusses the role of acetylcholinesterase (AChE) inhibition in the toxicity of organophosphorus (OP) and carbamate (CM) pesticides, with particular emphasis on lower doses that are sublethal, but induce changes in cholinergic receptors, either by indirect modulation of ACh levels via AChE inhibition or by direct interaction with the receptor. Case studies are presented that suggest that some of the toxicities associated with OP insecticides may not involve AChE or cholinergic receptors. Inhibition of AChE and subsequent cholinergic dysfunction represent a common mechanism of toxicity after acute exposure to high levels of OP and CM pesticides. However, the range of toxicities among different compounds is broad, and the potency of a compound for the inhibition of AChE is not a good predictor of its toxicity. Furthermore, toxicities associated with repeated exposures to lower levels of OPs do not correlate well with AChE inhibition. These observations suggest that significant interaction of OPs and CMs with other critical molecules within the cell may be important in explaining some of the toxicity of these compounds not attributable to AChE inhibition. Examples are presented with AChE null mice, direct interactions with muscarinic receptors and other molecules, impairment of cognitive development in weaning rats, OP-induced airway hyperreactivity mediated by M2 receptors, and direct effects on axonal growth in cell culture. The case studies provide strong evidence that noncholinesterase mechanisms are involved in the toxicity of OPs, and they have identified important gaps in the understanding of the mechanism of action of these important classes of insecticides.