In the last two decades, there have been increasing recognition of excess cases of end-stage renal disease (ESRD) requiring renal replacement therapy without common underlying causes (diabetes, hypertension, glomerulonephritis, or any identifiable cause) in many parts of low-to-middle income countries. ESRD of unknown etiology mainly affects young working-age adults and is a global health problem with substantial morbidity, mortality and disability. In this review, we provide a comprehensive overview of the burden and outcomes of treated ESRD attributable to unknown etiology in African countries. Estimates indicate that up to 71% of adults and up to 53% children on dialysis suffer from ESRD due to unknown etiology. ESRD of unknown etiology affects mostly the economically productive young adults, males and those from rural areas. ESRD due to unknown etiology carries an almost twofold risk of mortality compared to traditional ESRD causes and account for up to 55% of the renal medical admissions burden. This review confirms that treated ESRD due to unknown etiology is a major public health issue in Africa. Future studies are urgent need for better characterizing the regional causative factors as well as for developing proactive and comprehensive approaches to prevent and treat this under-recognized disease.