Over the past 7 decades, Mycobacterium tuberculosis has developed resistance to virtually every new drug used to treat tuberculosis, resulting recently in the global emergence of extensively drug-resistant tuberculosis. In an individual, treatment with a single new drug results in acquired drug resistance within weeks to months. On a population basis, the pattern is just as consistent. After a new drug is introduced, drug-resistant cases or case series are reported within months to years, typically leading to focused surveys, and within several years, dramatic outbreaks with extraordinary mortality occur. Invariably, such outbreaks prove to be the tip of the iceberg. Incomplete and delayed diagnoses, drug costs, and drug supplies are frequently implicated. With new drugs and new diagnostics on the horizon, we must develop new ways of incorporating them into public health practice, basing treatment on rapid drug-susceptibility tests, ensuring that effective drugs are always used in combination, and making these drug available to persons who need them.