Many of the receptors which are responsible for the responses to the common drugs of abuse belong to the G protein-coupled receptor (GPCR) family. In this special issue of the Journal of Neuroimmune Pharmacology a collection of papers is presented which deals with signaling events that are important for the function of these receptors. Because these receptors are expressed by both neuronal and immune cells, and because these receptors play a complex role in regulating function in both the nervous and immune systems, a more complete understanding of the regulation of expression of these receptors is essential. Moreover, once these receptors are expressed and activated, a complex series of signaling events are initiated that can have substantial significance. We have only a limited understanding of these signaling events, but with more complete information, we may be able to control the undesirable and/or desirable consequences of receptor activation by drugs of abuse.