Mammalian stress responses present a case study for investigating alternative splicing reactions in general, and changes in acetylcholinesterase (AChE) gene expression in particular, under endangered homeostasis. Acetylcholine (ACh) is a major regulator of stress responses, which was recently found to function as an essential route by which neurons can "talk" to immune cells. Therefore, chemical, physical, or psychological insults to the brain might all be traced in peripheral immune cells, which serve as key determinants in the physiological reactions to stress. Stress-induced changes in the alternative splicing patterns of AChE pre-mRNA give this gene and its different protein products diverse stress responsive functions that are associated with both the enzymatic and noncatalytic properties of AChE variants. Transgenic manipulations of AChE gene expression uncovered previously nonperceived aspects of stress responses, including brain-to-blood as well as immune-to-neuronal communication. Herein we discuss the newly gained understanding achieved by using genomic manipulations of AChE gene expression as tools for approaching the alternative splicing features of mammalian stress responses.