Mycobacterium tuberculosis is known as the most prevalent of mortality due to infection even with tuberculosis (TB) control programs. TB drug resistance has evolved and produced different strains of TB against numerous antimicrobial drugs, which has led to an increase in mortality. Resistant to Isoniazid and Rifampin is called multi-drug resistant TB (MDR-TB). And the resistant isolates to both first- and second-line antimicrobial factors have been recognized as extensively drug-resistant TB (XDR-TB). More than 90% of prevalence TB and its mortality occur in developing countries. Sistani and Baluchistan province has a high TB prevalence due to its proximity to Afghanistan and Pakistan. The aims of this review are investigating of the drug-resistant tuberculosis and risk factors related to TB. Also, treatment and epidemiology of the XDR-TB as a new challenge in TB control are described. And then epidemiology and incidence of TB are investigated in Sistan and Baluchestan Province. The main risk factors are previous treatment, age, HIV, male sex, alcoholism, smoking, poor socioeconomic, immigration and diabetes mellitus. To achieve success treatment and prevention of drug-resistant TB following World Health Organization (WHO) treatment guidelines extremely suggest. Due to the neighborhood of Iran with two countries Afghanistan and Pakistan that are among most polluted countries in the world, the more attention to this disease is strongly needed. To achieve the goals of the WHO, timely discovery and effective treatment of patients in each country, such as TB screening for exposed people and new methods of diagnosis and treatment of TB are needed.