The central nucleus of the amygdala (CeA) plays an important role in pain-related emotional responses and anxiety-like behavior. An emerging novel concept is that the amygdala also contributes to emotion-based cognitive deficits associated with pain. Cognitive impairment such as the inability to make advantageous decisions is one of the consequences of persistent pain but the underlying neural mechanisms are not known. The role of the prefrontal cortex in cognitive function, including decision-making and avoidance of emotion-based risky choices, is well established. Impaired prefrontal cortical function was recently shown in pain patients. A major source of input to the medial prefrontal cortex (mPFC) is the basolateral amygdala (BLA), a key element in the emotional-affective amygdala circuitry that also projects to the CeA. We hypothesize that the BLA contributes to pain-related emotional-affective behavior (through projections to the CeA) and cognitive deficits (through connections with the mPFC). Evidence from ongoing studies in our laboratory suggests that pain leads to CRF1 receptor-dependent central sensitization and synaptic plasticity in the BLA and increases inhibitory transmission from the BLA to mPFC neurons. Pain-related inhibition of mPFC neurons can be reversed by deactivating the BLA with a CRF1 receptor antagonist. Restoring normal function in the BLA by pharmacologic deactivation with a CRF1 antagonist improves pain-related decision-making deficits. We conclude that the amygdala impairs mPFC function resulting in pain-related decision-making deficits. Our data also suggest that CRF1 receptor antagonists may be useful tools to target affective and cognitive problems associated with pain.