Animal models have been used successfully to study various aspects of neural-immune interactions. Although different approaches carry certain advantages and disadvantages, current high sensitivity screening and manipulation methods coupled with molecular and genetic approaches can be successfully used to tease out the neural pathways that regulate inflammatory disease and the effects of immune molecules, such as interleukins, on neuronal function and pathology. Newer methodologies that measure gene expression of thousands of genes will in the future add to the ability to evaluate complex systems interactions in whole animal models. This review addresses the advantages and disadvantages of some of these approaches in the context of application to neural-immune interactions.