More than 44 million people live with diabetes in Africa. According to the International Federation of Diabetes, this number is expected to increase by 123% over the next decade. Africa has the most underdiagnosed diabetic patients worldwide. Together with an elevated mortality rate, this disease represents a serious socio-economic burden in the region. Thus, it is necessary to understand the underlying mechanisms of diabetes in African populations to develop better therapeutic strategies. Here, we focus on the importance of genetic background and the identification of biomarkers or druggable variants to provide tailored treatment for African patients with diabetes. First, we introduce the definition and physiopathology of different types of diabetes. In addition, we present the epidemiology of this disease in Africa to highlight its burden. Then, we report recent studies focusing on the genetic background of different types of diabetes and their utility in the diagnosis of the disease. Finally, we review the pharmacogenetic aspects of diabetes in different regions of Africa for better management of the disease. This chapter provides a better understanding of the genetic background of diabetes in Africa, which makes it the prime tool for African and worldwide physicians, endocrinologists, nutritionists, and researchers.