Abstract Dopamine (DA) transmission within cortical and subcortical structures is involved critically in the processing of emotionally relevant sensory information. Three interconnected neural regions, the medial prefrontal cortex (mPFC), basolateral nucleus of the amygdala (BLA) and the ventral tegmental area (VTA) have received considerable experimental attention, both in animal and clinical research models, as essential interconnected processors of emotional information. Neuronal network activity within both the mPFC and BLA are strongly modified by DA inputs from the VTA through both DA D2-like and D1-like receptors. However, emerging evidence from clinical, genetic, behavioral and electrophysiological investigations demonstrates a critical role for the DA D4-receptor subtype as a crucial modulator of emotional memory encoding and expression, both at the level of the single neuron, and at the systems level. In this review, we will examine recent evidence at the neuronal, behavioral and genetic levels of analysis that increasingly demonstrates an important role for DA D4 transmission within cortical and subcortical emotional processing circuits. We will present evidence and some theoretical frameworks suggesting how disturbances in D4-receptor related neural circuitry may be involved in the neuropathological manifestations common in many neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder (ADHD) and addiction.