Chronic pain is a global health problem that remains inadequately understood and poorly managed by current existing therapies. Although decades of functional human imaging studies have shown that the overall pain experience results from a collective output activity arising from a matrix of brain networks including the sensory, cingulate and prefrontal cortices, understanding the circuits and cellular contributions towards pain chronicity have only recently began to emerge. Using multidisciplinary approaches such as optogenetics, chemogenetics, imaging, in vivo electrophysiology and functional activity mapping, I will discuss the specificity and functional causality of novel pathways and mechanisms of nociceptive processing in the brain.