Stimulation of Group I metabotropic glutamate receptors (mGluR1 and mGluR5) leads to activation of a wide variety of signalling pathways. mGluRs couple to Gα(q/)₁₁ proteins, activating phospholipase Cβ1 resulting in both diacylglycerol and inositol-1,4,5-triphosphate formation followed by the activation of protein kinase C. In addition, mGluR activation can lead to modulation of a number of ion channels, such as different types of calcium and potassium channels. Group I mGluRs can also activate other downstream protein kinases, such as ERK1/2 and AKT, which are implicated in cellular growth, differentiation, and survival. Moreover, Group I mGluRs interact with a variety of different proteins that are important for the regulation of synaptic signalling, such as Homer and PDZ domain containing proteins, such as Tamalin. A role for mGluR1/5 in a number of disease states has also been proposed. As mGluR1/5 signal transduction is complex and involves multiple partners, a better understanding of alterations in mGluR signalling in brain disorders will be required in order to discern the molecular and cellular basis of these pathologies. This review will highlight recent findings concerning mGluR signaling alterations in brain pathologies, such as stroke, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and drug addiction.