Research consistently finds that men use all types of drugs more frequently and extensively than women. However, the misuse of prescription tranquilizers provides an exception. Recent research has found that women are more likely to misuse tranquilizers than men, yet few efforts have been made to systematically understand why this is the case and whether there are gendered factors that might help explain their misuse. Building on general strain theory and other scholarship concerning the links between psychological strain, mental–emotional health, and illicit drug use, we employed a mixed-methods design to investigate the interrelationships between gender, mental health, and tranquilizer misuse. Using data from the 2010 National Survey of Drug Use and Health, we examined tranquilizer misuse among women using various social, demographic, and health-related characteristics. Following this, we drew on nine in-depth interviews with adult women aged 21 to 69 years who reported a history of misusing tranquilizers. The quantitative data reveal that the odds of tranquilizer misuse are nearly two times higher for each unit increase on the poor mental health scale. Whereas being married increases the risk of misuse, having young children is associated with a decreased risk. Our analysis of the interview data reveals three main themes, related to tranquilizer access, reasons for misuse, and shame related to misuse. The interviews clearly uncover tranquilizer misuse as an attempt by women to manage competing demands between their work and home lives, and more specifically as a means of promoting success in both devotions. We conclude by arguing that women’s misuse of tranquilizers is a gendered behavior in response to gender-specific strains, which in turn reproduces gendering as an institution as well as in individual lives. The implications of these findings for general strain theory are also discussed.