The interface of receptor-mediated regulation of cellular signaling and neurological outputs remains an active field of investigation. The metabotropic G protein-coupled glutamate receptors, and in particular, the group II cyclic adenosine mono-phosphate (cAMP)-lowering metabotropic glutamate receptors 2 and 3 (mGlu2/3 glutamate receptors), have gained interest as therapeutic targets in different forms of neurological disorders. This review explores mGlu2/3 glutamate receptors expression, pharmacological activation, and signaling links to anxiety, as assessed in animal models and in clinical trials.