Among the 8 cloned metabotropic glutamate receptors (mGluRs), the group III receptors (4,6,7,8) have thus far received the least attention in terms of their therapeutic potential. This can be attributed to the paucity of available selective ligands for these targets. However, recently, there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably for their role in modulating neurotransmission in the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson's disease (PD). In addition, recent reports also have detailed the neuroprotective effects of an mGluR4 positive allosteric modulator (PAM) in cultured neurons and in vivo. ML128 (CID-44191096) is a highly optimized mGluR4 in vitro and in vivo probe and now represents the most potent and selective of mGluR4 PAM identified to date. Furthermore, ML128 is only mGluR4 PAM that is centrally penetrant upon systemic dosing, while also displaying excellent pharmacokinetics and anti-Parkinsonian activity in a preclinical rodent model of PD.