This interdisciplinary dissertation in anthropology and social work examines the intersections of HIV/AIDS and kinship and its impact on orphan care and the family in rural Lesotho. It presents findings from 14 months of ethnographic fieldwork between 2007 and 2009 in the rural district of Mokhotlong, Lesotho. Data collection methods included a series of 3 to 5 semi-structured interviews with 21 caregivers, interviews with other community members and health care providers, household survey data collection, archival research, participant observation and field notes. In the context of the AIDS pandemic, I explore the physical, material, and emotional challenges of orphan care; the difficulties of treatment in a rural southern African context with a focus on the intersection of biomedical beliefs and practices with social and cultural ones; and the reorganization of families as a result of these factors. I find that HIV is fundamentally a kinship disease. My work affords a micro-level view into the everyday strategies of household caregiving practices that showcases Basotho families’ experiences of AIDS and the sometimes contradictory meanings and practices that emerge in the intimate spaces of family life. I provide a framework for rethinking the ways that a biocultural approach to HIV/AIDS undergirds the negotiations people make between idealized rules of kinship and everyday practices in caring for orphans. The findings of this study support several recommendations for the design and development of interventions. From a broad theoretical perspective, this research suggests that: 1) interventions need to recognize the deeply embedded nature of HIV and kinship, and 2) there are malleable cultural resources, such as idealized notions about gender, that are in fact flexible and are strategically deployed to respond to the challenges of HIV/AIDS. The three empirical findings for the design and development of interventions recommend that: 1) interventions for AIDS orphans need to include caregiver support, 2) the household should be considered as a salient unit of analysis, evaluation and intervention and, 3) biomedical or biocultural interventions for HIV/AIDS need to incorporate the underlying theoretical framework of HIV as a kinship disease in order to be effective.