The prefrontal cortex (PFC) is considered a critical node in the neural circuitry underlying drug-seeking behaviors. However, the mechanisms by which this region influences drug seeking and whether or not the lateral PFC mediates cocaine or heroin seeking are questions that have yet to be answered. To expand on the role of the PFC in drug seeking, rats were trained on either heroin or cocaine self-administration for a minimum of 12 days before undergoing extinction training and subsequent reinstatement tests (cued and drug-prime). All pharmacological manipulations were delivered immediately prior to reinstatement testing and were targeted at either the ventral region of the medial PFC, the infralimbic cortex (IL), the anterior portion of the medial PFC, the medial orbitofrontal cortex (mOFC), the anterior region of the insular cortex, the dorsal agranular insular cortex (AId), or the posterior region of the insular cortex, the posterior insular cortex (PIc). In chapter 1, D1 and D2 antagonists were administered into the IL and mOFC prior to cued and cocaine-prime reinstatement. Although previous studies found that the IL inhibits cocaine seeking, blocking D1 receptor activity in this region reduced cued reinstatement and had no effect on cocaine-prime reinstatement, indicating that the IL can promote cocaine seeking under certain circumstances. In contrast, blocking D1 receptors in the mOFC reduced all forms of reinstatement that were examined. Blocking D2 receptors in either region had no effect on cocaine seeking. Our data are the first to demonstrate a role for the mOFC in cocaine seeking and suggest that although the IL and mOFC lie immediately adjacent to one another, they play distinct roles in mediating cocaine seeking. In chapter 2, we pharmacologically inactivated the AId and PIc via a GABA agonist administered immediately prior to both cocaine and food seeking. Reversible inactivation of the AId reduced cued reinstatement but had no effect on cocaine-prime reinstatement. In contrast, inactivating the PIc had no effect on any form of cocaine seeking. Additionally, blocking the AId during cued and food-prime reinstatement had no effect on food seeking, indicating the role of the AId in reinstatement is specific to cocaine seeking and not general motivated behavior. Additionally, blocking CRF1 receptors in the AId blocked cued reinstatement, suggesting a possible mechanism whereby the AId is influencing cocaine seeking. These data are the first to establish a role for the AId in cocaine seeking and demonstrate that although the PIc influences alcohol and nicotine seeking, it does not mediate cocaine seeking. Chapter 3 further examined the role of the AId in cocaine seeking and expanded the influence of the insular cortex in drug seeking to heroin. AId D1 receptor blockade reduced both cued and cocaine-prime reinstatement following extinction training, whereas D2 receptor blockade had no effect on cocaine seeking. These results establish a role for the AId in cocaine-prime reinstatement, as pharmacological inactivation showed no role for the AId in cocaine-induced drug seeking. Additionally, blocking the AId during heroin seeking potentiated cued reinstatement whereas blocking the PIc during heroin seeking reduced cued reinstatement. These results demonstrate a role for the insular cortex in heroin seeking that has never been shown before and further explain how the AId may be influencing cocaine seeking.