This article traces the historical evolution of conditions that favoured the spread of HIV in Rakai district, Uganda, and the process of evolution of the local, popular epidemiology of HIV and AIDS. It argues that the HIV epidemic was made possible by economic and social disparities, which grew more pronounced since the mid-1970s as a result of economic decline, physical insecurity, and the disbanding of public services. The local constructions of AIDS in Rakai have changed and shifted according to the progress of the epidemic, eventually challenging the initial cultural construction of the disease, based on local notions about causality between disease and morality. The progress of the epidemic undermined the local intellectual authority (e.g. traditional healers, health workers, and religious leaders), creating a need to produce additional explanations of the disease. The concept of 'Slim' in Rakai emerged as a popular construct to denote the physical, psychological and social consequences of HIV disease. The concept reflects popular concerns over the outcomes of the epidemic rather than its cause, being more concerned about the fate of individuals and communities than about issues of morality. Later, the moral construction of 'Slim' that accompanied the biomedical categorisation of AIDS as a sexually transmitted disease made it appear as a disease of sexual indulgence and promiscuity. The bio-moral construction of 'Slim' was also challenged by local evangelical claims about the power of faith and morality to regenerate its 'victims,' something that biomedicine had not been able to provide. As the disease has become part of the social ecology of Rakai and the rest of Uganda, interpretations of it will continue to be challenged and reconstructed.