Mycobacterium tuberculosis is an extraordinarily successful human pathogen, infecting one-third of the world's population and causing nearly two million deaths each year. In this article, current trends in worldwide tuberculosis (TB) incidence, prevalence, and mortality are discussed along with standard TB treatment regimens, characteristics of first-line and second-line anti-tuberculosis drugs, and mechanisms of antibiotic resistance. The global TB emergency has been further exacerbated by extensively drug-resistant (XDR) TB strains that are resistant to our best antibiotics and very difficult to treat. This review also focuses on the emergence of XDR-TB strains, the global health impact, and existing treatment options and outcomes for XDR-TB disease. Finally, this review briefly describes new anti-tuberculosis drugs currently in Phase II clinical evaluations and the impetus for discovering new antibacterial compounds to target drug-resistant M. tuberculosis and improve tuberculosis therapy.