It has long been recognized that as societies modernize, they experience significant changes in their patterns of health and disease. Despite rapid modernization across the globe, there are relatively few detailed case studies of changes in health and disease within specific countries especially for sub-Saharan African countries. This paper presents evidence to illustrate the nature and speed of the epidemiological transition in Accra, Ghana’s capital city. As the most urbanized and modernized Ghanaian city, and as the national center of multidisciplinary research since becoming state capital in 1877, Accra constitutes an important case study for understanding the epidemiological transition in African cities. We review multidisciplinary research on culture, development, health, and disease in Accra since the late nineteenth century, as well as relevant work on Ghana’s socio-economic and demographic changes and burden of chronic disease. Our review indicates that the epidemiological transition in Accra reflects a protracted polarized model. A “protracted” double burden of infectious and chronic disease constitutes major causes of morbidity and mortality. This double burden is polarized across social class. While wealthy communities experience higher risk of chronic diseases, poor communities experience higher risk of infectious diseases and a double burden of infectious and chronic diseases. Urbanization, urban poverty and globalization are key factors in the transition. We explore the structures and processes of these factors and consider the implications for the epidemiological transition in other African cities.