Drug-resistant microorganisms have become a major problem around the world. In nosocomial and community settings, many important pathogens have demonstrated high-grade resistance to many of our most important agents. In addition, the adverse impact of resistance has not been limited to the bacterial realm. In chemotherapy to treat human immunodeficiency virus (HIV) and other viral diseases, resistance has become a major problem. We are starting to see the beginnings of a resistance problem, even among fungi. Strangely, little attention has been focused on the impact of dosing on the probability with which emergence of resistance occurs. After delineation of the pharmacodynamically linked variable, it is possible to generate dosing regimens that can lower the probability of resistance. In addition, circumstances exist in which combination therapy may be required (e.g., therapy of HIV and tuberculosis). Here, too, it is possible to optimize therapy to prevent resistance by understanding how the drugs in the regimen interact. We can do better with our choices of dose, schedule, and combinations of agents. We will need to lower the probability of resistance and maintain the utility of the drugs currently in our therapeutic armamentarium.