Pharmacokinetic characteristics and pharmacodynamic properties dictate antimicrobial response and, along with natural immune responses, clinical outcomes. As new agents are developed with long half-lives, we will lose the ability to differentiate between concentration-dependent and time-dependent properties. The area under the inhibitory concentration curve (AUIC) defines drug regimens as a ratio of drug exposure to minimum inhibitory concentration (MIC) and allows them to be compared with each other. With AUIC and agents with long half-lives, these comparisons are possible regardless of chemical classification or concentration or time-dependent activity. Historical examples of reduced drug exposure from decreased doses (i.e., cefaclor, clarithromycin, and ciprofloxacin), and thus low AUIC values, directly correlate with drug resistance. In the face of rising MICs (as is occurring worldwide with Streptococcus pneumoniae), close attention to appropriate dosing and concentration above the MIC may delay and potentially even prevent antibiotic resistance. Creating selective pressure on reliable antibiotics by inappropriately reducing their doses will undoubtedly challenge these agents and may destroy entire drug classes with similar mechanisms of action or resistance.