Prevention and control of tuberculosis in middle and low income countries is a great challenge for health care workers as well as funding agencies. Issues which pose challenges in these countries are different from the developed world and hence need to be addressed in a different manner. Key challenges remain; high prevalence of tuberculosis especially drug resistant tuberculosis, Multidrug Resistant Tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB), Human Immunodefiency Virus (HIV) and TB co morbidity, local, social and structural factors (which are different from region to region), economic constrains, poor diagnostic facilities etc. To meet these challenges, building a strategy on case management, maintaining high quality of care and preventing drug resistance, building human resource capacity, improving diagnosis and fostering operation research in area of tuberculosis should be the health care priority in these countries. Here, we have focused on each one of the important issues which adversely impact the control and prevention of tuberculosis in economically weaker countries.