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In the last decade, the fields of HIV/AIDS prevention, care, and surveillance have experienced fundamental transformations driven primarily by new health information technologies (IT) and pharmacological advances. During this period, social scientific and humanistic studies of HIV/AIDS and biomedicine, sexuality and AIDS, the criminalization and surveillance of people living with HIV, and the licit and illicit drugs associated with the AIDS epidemic have similarly experienced a renaissance. In this paper, I argue that new realities stemming from changes in regimes of truth about AIDS call for novel approaches that can account for what I call “contemporary metastrucutral issues” and “irresolvable problems” that structure the AIDS epidemic and inquiries into it. Drawing upon theories of “materialization” and “reality,” I argue that HIV researchers should assume a “transversal orientation” toward HIV: a mode of inquiry that can analytically operate across multiple scales, and which can adequately describe the vastly different and potentially limitless sets of systems and actors that are involved in the production of realities shaped by HIV (from World Health Organization standards to local teams of data entry staff). I take cues from a transnational group of scholars and practitioners who have called for and contributed to new paradigms in the study of HIV/AIDS and its effects on sexuality, medicine, individuals, (sub)cultures, and societies. The paper draws upon extensive ethnography and health policy research with practitioners in Metropolitan Atlanta and among U.S. federal policymakers, as well as my experience building a nonclinical HIV testing program.