Chronic pain is induced by tissue or nerve damage and is accompanied by pain hypersensitivity (i.e., allodynia and hyperalgesia). Previous studies using two-photon microscopy have shown functional and structural changes in the primary somatosensory (S1) cortex at the cellular and synaptic levels in inflammatory and neuropathic chronic pain. Furthermore, alterations in local cortical circuits were revealed during the development of chronic pain. In this review, we summarize recent findings regarding functional and structural plastic changes of the S1 cortex and alteration of the S1 inhibitory network in chronic pain. Finally, we discuss potential neuromodulators driving modified cortical circuits and suggest further studies to understand the cortical mechanisms that induce pain hypersensitivity.