Metabotropic glutamate receptors represent an exciting new target for the treatment of a wide variety of diseases, including psychiatric and neurological diseases such as Parkinson's disease, schizophrenia, anxiety, pain and drug addiction. These receptors are structurally more complex than other GPCRs, being mandatory dimers. Each subunit is composed of two main domainsâ a large extracellular domain where agonists bind and a 7TM domain responsible for G protein activation. Such complex proteins offer a variety of possibilities to develop new drugs, either acting at the glutamate site (orthosteric agonists and antagonists) and allosteric compounds possibly interacting at various sites, either in the 7TM domains or in the extracellular domain. This chapter summarizes current views on the activation mechanisms and regulation of these receptors, and how these may impact the more general field of GPCRs.