Clinical and preclinical research have identified sex differences in substance use and addiction-related behaviors. Historically, substance use disorders are more prevalent in men than women, though this gap is closing. Despite this difference, women appear to be more susceptible to the effects of many drugs and progress to substance abuse treatment more quickly than men. While the glutamate system is a key regulator of addiction-related behaviors, much of the work implicating glutamate signaling and glutamatergic circuits has been conducted in men and male rodents. An increasing number of studies have identified sex differences in drug-induced glutamate alterations as well as sex and estrous cycle differences in drug seeking behaviors. This review will describe sex differences in the glutamate system with an emphasis on implications for substance use disorders, highlighting the gaps in our current understanding of how innate and drug-induced alterations in the glutamate system may contribute to sex differences in addiction-related behaviors.