The encoding of negative valence in response to noxious stimuli/experiences and in turn, the behavioral representation of negative affective states is essential for survival. Recent advances in neuroscience have determined multiple sites of neural plasticity and key circuits of connectivity across these regions in mediating aversive behavior. G protein-coupled receptors (GPCRs), owing to their neuromodulatory role, are especially important to refining our understanding of the molecular substrates involved in these circuits. In this review, we will focus on recent, contemporary findings that explore neural circuit-specific roles for neurotransmitter/peptide GPCRs and the importance of using novel approaches to illuminate the molecular mechanisms central to aversive learning.