In this introduction to the special issue, we follow the journey of global AIDS medicines into diverse health facilities in East Africa, which for decades have been subjected to neoliberal reform processes and increasing fragmentation. The introduction explores the multifaceted and multidirectional connections between global processes and their manifold articulations and experiences “on the ground.” We sketch how individuals, families, and communities dealt with HIV/AIDS-related illness and death before the scale-up of life-prolonging antiretroviral therapy programs, and describe the global policy processes that led to an influx of large volumes of donor support for AIDS treatment programs. We argue that global AIDS medicines have caused dramatic changes in institutional set-ups and care practices. The pharmaceutical medicines travel to the local health care settings with “baggage”: protocols and guidelines on who to treat and why, with strict guidelines on how to ensure adherence; and new notions of responsible and therapeutic citizens. This special issue elucidates the frictions, negotiations, and ambiguities that have shaped the incorporation of global AIDS medicines in local healthcare settings.