Gender and HIV risk have been widely examined in southern Africa, generally with a focus on dynamics within sexual relationships. Yet the social construction of women’s lives reflects their broader engagement with a gendered social system, which influences both individual-level risks and social and economic vulnerabilities to HIV/AIDS. Using qualitative data from Lesotho, we examine women’s lived experiences of gender, family and HIV/AIDS through three domains: 1) marriage; 2) kinship and social motherhood, and 3) multigenerational dynamics. These data illustrate how women caregivers negotiate their roles as wives, mothers, and household heads, serving as the linchpins of a gendered family system that both affects, and is affected by, the HIV/AIDS epidemic. HIV/AIDS interventions are unlikely to succeed without attention to the larger context of women’s lives, namely their kinship, caregiving, and family responsibilities, as it is the family and kinship system in which gender, economic vulnerability and HIV risk are embedded.