Nicotine dependence is the primary motivational factor perpetuating the tobacco smoking habit that is one of the leading preventable causes of morbidity throughout the world. This Neuroscience Perspectives article summarizes and discusses recent evidence demonstrating the critical role of glutamate transmission in nicotine dependence and emerging data suggesting that compounds acting as antagonists at metabotropic glutamate receptors may be useful therapeutics to assist people in achieving and maintaining abstinence from tobacco smoking. Metabotropic glutamate 5 receptor antagonists may be useful in decreasing the reinforcing effects of nicotine, reducing motivation for nicotine and preventing relapse during protracted abstinence, whereas metabotropic glutamate 2/3 receptor antagonists may alleviate the depression observed during the early nicotine withdrawal phase. Metabotropic glutamate 2/3 receptor antagonists may also be therapeutics for non-drug-induced depressions.