This review discusses the role of aberrant neuroimmune functioning in chronic pain disorders. Like other negatively-valenced emotions, pain activates a complex adaptive response that includes endocrine, autonomic and immune components. When appropriate, this response re-establishes homeostasis. However, in the context of chronic pain dysregulated immune, autonomic and endocrine responses contribute to peripheral and central sensitization, a phenomena emblematic of chronic pain. Excessive neuroimmune interactions in the vicinity of nociceptors and in dorsal root ganglia augment peripheral pain-related transmission. These amplified peripheral signals are associated with increased immune/inflammatory signaling in the dorsal horn and supraspinal pain-processing circuitry, the so-called “pain maitrix”. We focus on the neuron-glia-immune cell junction as the principal processing unit of pain signals in the CNS. Neuroimmune disturbances not only have functional consequences, such as amplified pain signaling, but also contribute to structural alterations in pain-processing brain areas. Lastly, aberrant immune activation also participates in dysfunctional descending pain regulation. The role of the immune system as a meta-homeostatic entity that coordinates interactions of emotion- and stress-modulating brain circuitry with endocrine and autonomic systems is discussed in some detail. We emphasize the importance of neuroimmune mechanisms not only in the genesis but also in treatment of chronic pain.