Although fluoroquinolones (FQs) play an important role in the treatment of multidrug-resistant tuberculosis (MDR-TB), there are several issues that need to be addressed to optimize their effectiveness and minimize toxicity. This includes identification of the optimal dose of FQs such as levofloxacin (LVX) and moxifloxacin, and the optimal role of FQs in combination with other anti-tuberculosis drugs, particularly those with overlapping toxicity, such as QT prolongation. While the ability of FQs to penetrate into cavities and granulomas is likely beneficial, suboptimal sensitivity of genotypic tests to detect FQ resistance could negatively affect treatment outcomes of FQ-containing regimens. Several trials are underway to evaluate the safety and effectiveness of FQs as part of combination MDR-TB therapy; there are also two planned studies of LVX to prevent tuberculosis among close contacts of MDR-TB.