Chronic pain is a prevalent and debilitating condition, conveying immense human burden. Suffering is caused not only by painful symptoms, but also through psychopathological and detrimental physical consequences, generating enormous societal costs. The current treatment armamentarium often fails to achieve satisfying pain relief; thus, research directed toward elucidating the complex pathophysiological mechanisms underlying chronic pain syndromes is imperative. Central neuroimmune activation and neuroinflammation have emerged as driving forces in the transition from acute to chronic pain, leading to central sensitization and decreased opioid efficacy, through processes in which glia have been highlighted as key contributors. Under normal conditions, glia exert a protective role, but in different pathological states, a deleterious role is evident—directly and indirectly modulating and enhancing pain transmission properties of neurons, and shaping synaptic plasticity in a dysfunctional manner. Cytokines and neurotrophic factors have been identified as pivotal mediators involved in neuroimmune activation pathways and cascades in various preclinical chronic pain models. Research confirming these findings in humans has so far been scarce, but this comprehensive review provides coherent data supporting the clear association of a mechanistic role of altered central cytokines and neurotrophic factors in a number of chronic pain states despite varying etiologies. Given the importance of these factors in neuropathic and inflammatory chronic pain states, prospective therapeutic strategies, and directions for future research in this emerging field, are outlined.