For 25 years we have studied the molecular neurobiology, pharmacology, and toxicology of cholinesterases, including the role of these enzymes in normal cholinergic neurotransmission and their involvement in disease. Early on we produced monoclonal antibodies that selectively destroyed cholinergic pathways in rats. That unexpected effect led to a unique animal model, which shed light on the normal workings of the sympathetic nervous system and on neuroimmunology. We now focus on cholinesterases as biological targets of drugs, chemical warfare agents, and pesticides, and also as active participants in neurologic disorders. Our recent data show that acetylcholinesterase can promote deposits of brain amyloid in Alzheimer's disease. Working with other Mayo investigators we designed new anticholinesterases to block this pathologic effect and we created a novel line of transgenic mice to test their therapeutic potential. Our latest work involves molecular modeling and rational mutagenesis to convert cholinesterases themselves into clinically useful agents. This approach has already produced novel enzymes that hydrolyze cocaine fast enough to be candidates for treating drug overdose. Now we are evaluating the possibility that viral gene transfer of these enzymes could suppress psychological and behavioral responses to cocaine. A long-term goal is to develop molecular agents that might aid addicts in drug cessation programs.