The therapy of mycobacterial infections is challenging for a number of reasons. Because mycobacteria are not susceptible to many classes of antibacterial agents, treatment typically requires the use of antimicrobial drugs that are not commonly used and may have small therapeutic windows. For many species, procedures for drug susceptibility testing and optimal treatment regimens have yet to be defined. Finally, because mycobacteria are generally slow to succumb to antimicrobial agents, therapy must be given with multiple drugs for prolonged periods of time, making it necessary to monitor for drug toxicity, drug interactions, and patient nonadherence. Better understanding of the pharmacokinetics and pharmacodynamics of antimycobacterial agents should improve the therapy of mycobacterial infections. Using current treatment strategies for tuberculosis and Mycobacterium avium complex infections as examples, this review highlights basic pharmacokinetic and pharmacodynamic principles and the rationale for combination chemotherapy that should also be applicable to other mycobacterial infections.