Tuberculosis (TB) treatment has changed little in the past 40 years. The current standard therapy requires four drugs for 2 months followed by two drugs for 4 months. This "short-course" regimen is not based on optimized pharmacokinetic and pharmacodynamic properties, but empiric evidence. A review of existing data suggests that pharmacokinetic variability with isoniazid and rifampin is greater than previously thought, and that efficacy is not as good as traditionally reported. Adding new drugs to the current regimen will be costly and time-consuming. Maximizing the efficacy of the current medications is a less expensive and more feasible option. This article reviews the current potential of the first-line TB drugs (rifamycins, isoniazid, pyrazinamide, and ethambutol) as well as the fluoroquinolones to introduce a true short-course TB regimen.