Substance use disorders (SUDs) are debilitating neuropsychiatric conditions that exact enormous costs in terms of loss of life and individual suffering. While much progress has been made defining the neurocircuitry and intracellular signaling cascades that contribute to SUDs, these studies have yielded limited effective treatment options. This has prompted greater exploration of non-traditional targets in addiction. Emerging data suggest inputs from peripheral systems, such as the immune system and the gut microbiome, impact multiple neuropsychiatric diseases, including SUDs. Until recently the gut microbiome, peripheral immune system, and the CNS have been studied independently; however, current work shows the gut microbiome and immune system critically interact to modulate brain function. Additionally, the gut microbiome and immune system intimately regulate one another via extensive bidirectional communication. Accumulating evidence suggests an important role for gut-immune-brain communication in the pathogenesis of substance use disorders. Thus, a better understanding of gut-immune-brain signaling could yield important insight to addiction pathology and potential treatment options. Copyright © 2021 Elsevier Inc. All rights reserved.