This article synthesizes recent data suggesting that the high rates of comorbidity observed between major depression, fibromyalgia and neuropathic pain likely result from the fact that these disorders share multiple biological and environmental underpinnings. This perspective suggests that these biologically complex conditions result from similar genetic vulnerabilities interacting with environmental adversity. Shared genetic determinants include poorly functional alleles regulating monoaminergic, glutamatergic, neurotrophic, opioid and inflammatory cytokine signaling. Chief among environmental risk factors are psychosocial stress and illness, both of which promote, in vulnerable individuals, relative resistance to glucocorticoids, increased sympathetic/decreased parasympathetic activity and increased production and release of proinflamnmatory mediators. Dysregulation of stress/inflammatory pathways promotes alterations in brain circuitry that modulates mood, pain and the stress response. Over time, these functional changes likely promote disruptions in neurotrophic support and disturbances of glia-neuronal communication. These changes, in turn, have been associated with the related processes of central sensitization in pain disorders and "kindling" in depression, both of which may account for the progressive and self-perpetuating nature of these disorders, especially when inadequately treated.