The article discusses the role of neuroinflammation and central sensitization in chronic and widespread pain. Neuroinflammation, characterized by the activation of glial cells (microglia and astrocytes) and the release of pro-inflammatory cytokines and chemokines, is a key driver of chronic pain. Central sensitization, a phenomenon of synaptic plasticity and increased neuronal responsiveness in pain pathways, is closely linked to neuroinflammation. The activation of glial cells leads to the production of cytokines and chemokines, which modulate synaptic plasticity and enhance pain sensitivity. These mediators play a crucial role in maintaining chronic pain and contributing to its widespread nature. The article also highlights sex-dependent differences in glial regulation of pain and discusses therapeutic approaches targeting neuroinflammation and central sensitization to manage chronic pain. Despite some promising clinical trials, there are challenges and limitations, such as the lack of biomarker validation and sex-dependent effects, that need to be addressed in future research.The article discusses the role of neuroinflammation and central sensitization in chronic and widespread pain. Neuroinflammation, characterized by the activation of glial cells (microglia and astrocytes) and the release of pro-inflammatory cytokines and chemokines, is a key driver of chronic pain. Central sensitization, a phenomenon of synaptic plasticity and increased neuronal responsiveness in pain pathways, is closely linked to neuroinflammation. The activation of glial cells leads to the production of cytokines and chemokines, which modulate synaptic plasticity and enhance pain sensitivity. These mediators play a crucial role in maintaining chronic pain and contributing to its widespread nature. The article also highlights sex-dependent differences in glial regulation of pain and discusses therapeutic approaches targeting neuroinflammation and central sensitization to manage chronic pain. Despite some promising clinical trials, there are challenges and limitations, such as the lack of biomarker validation and sex-dependent effects, that need to be addressed in future research.