This dissertation examines sex differences in response to cocaine, with a focus on how the female reproductive cycle and ovarian hormones explain the sexually differentiated clinical profile of cocaine dependence. Presented here are studies that examine the hypothesis that sex differences in cocaine seeking, including the choice of cocaine over a competing reinforcer, are explained by either the short or long term effects of ovarian hormones. Specifically, these studies examine the role of sex, estrous cycle phase, ovarian hormone status, and estrogen on several reinforcement measures with the following research aims: (1) determine if sex and estrous effects in cocaine seeking are present after long-term drug abstinence; (2) determine if the effects of sex and estrous generalizes to food seeking; (3) determine if there is an impact of sex and estrous on the negative effects of cocaine; (4) determine the role of sex, estrous, ovariectomy, and estrogen on selection between food and cocaine. It is demonstrated that the effects of sex and estrous are enduring, do not generalize to food, are impacted by both the positive and negative effects of cocaine, and the long-term effects of estrogen are critical for females selecting cocaine over food more often than males. Therefore, the results of these studies suggest that both the immediate and long-term mechanisms of ovarian hormones contribute to sex differences in a variety of reinforcement measures. These findings are discussed individually within the context of current literature on sex differences in appetitive responses as well as how the results reflect upon each other to inform future projects.