Antimicrobial resistance among respiratory tract pathogens represents a significant health care threat. Identifying the antimicrobial agents that remain effective in the presence of resistance, and knowing why, requires a thorough understanding of the mechanisms of action of the various agents as well as the mechanisms of resistance demonstrated among respiratory tract pathogens. The primary goal of antimicrobial therapy is to eradicate the pathogen, via killing or inhibiting bacteria, from the site of infection; the defenses of the body are required for killing any remaining bacteria. Targeting a cellular process or function specific to bacteria and not to the host limits the toxicity to patients. Currently, there are four general cellular targets to which antimicrobials are targeted: cell wall formation and maintenance, protein synthesis, DNA replication, and folic acid metabolism. Resistance mechanisms among respiratory tract pathogens have been demonstrated for all four targets. In general, the mechanisms of resistance used by these pathogens fall into one of three categories: enzymatic inactivation of the antimicrobial, prevention of intracellular accumulation, and modification of the target site to which agents bind to exert an antimicrobial effect. Resistance to some agents can be overcome by modifying the dosage regimens (e.g., using high-dose therapy) or inhibiting the resistance mechanism (e.g., b-lactamase inhibitors), whereas other mechanisms of resistance can only be overcome by using an agent from a different class. Understanding the mechanisms of action of the various agents and the mechanisms of resistance used by respiratory tract pathogens can help clinicians identify the agents that will increase the likelihood of achieving optimal outcomes.