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The nervous and immune systems have complementary roles in the adaptation of organisms to environmental changes. However, the mechanisms that mediate cross-talk between the nervous and immune systems, called neuroimmune interactions, are poorly understood. In this Review, we summarize advances in the understanding of neuroimmune communication, with a principal focus on the central nervous system (CNS): its response to immune signals and the immunological consequences of CNS activity. We highlight these themes primarily as they relate to neurological diseases, the control of immunity, and the regulation of complex behaviours. We also consider the importance and challenges linked to the study of the neuroimmune connectome, which is defined as the totality of neuroimmune interactions in the body, because this provides a conceptual framework to identify mechanisms of disease pathogenesis and therapeutic approaches. Finally, we discuss how the latest techniques can advance our understanding of the neuroimmune connectome, and highlight the outstanding questions in the field.