It was not many years ago when WHO declared the eradication of smallpox triumphantly. There was a sense of optimism that the long struggle for control over infectious diseases will come to an end within the 20th century. Such optimisms, however turned into a fatal complacency when the 21st century is just around the corner. Infectious diseases such as diarrheal diseases, acute pulmonary infections and malaria remain the leading cause of death in Africa. Moreover, newly-appearing infectious diseases (emerging diseases) and diseases that are spreading to new geographical areas and diseases which have developed anti-microbial resistance (re-emerging diseases) are threatening the health of World's population. Among these diseases AIDS is the most dramatic example as it affects over 23 million people, mainly targetting the economically productive age group of 15-50 years, in sub-Saharan African countries. The incidence of malaria, cholera, tuberculosis, schistosomiasis and other infectious diseases also show no tendency to decrease and are still raging in sub-Saharan Africa. Many background factors such as rapid population growth and urbanization, changes in lifestyle and behavior, increase of refugees due to ethnic conflicts, poverty, poor hygiene and sanitation conditions, deforestation, greenhouse effect, development of anti-microbial resistant pathogens as well as the North-South problem and the uneven distribution of wealth within the country spur on this tendency. In addition to the discovery of new drugs and the development of vaccines, improvement of sanitation systems with better understanding of infectious diseases and also the re-evaluation of traditional medicine and the ingenious knowledge while invoking people's endeavor for self-help are more important to control over fatal diseases in Africa in the 21st century.