Antimicrobial resistance is frequently associated with clinical use of antibiotics. This close association suggests that efforts to manage our use of these potent agents can have an impact on the prevalence of resistance. Unfortunately, one size does not fit all when considering the response of bacterial pathogens to antimicrobial exposure. Measures that may prevent resistance in some species (such as using multiple antibiotics to treat tuberculosis) may exacerbate the problem of resistance in others (such as Pseudomonas aeruginosa or Acinetobacter baumannii). The simplest approach is to use fewer antibiotics and thereby apply less selective pressure to the prevalent flora. Among available strategies to reduce use, reductions in length of antimicrobial regimens are the safest and are likely to be the most palatable to practicing clinicians. Studies are urgently needed to define minimal lengths of therapy to ensure that efforts at reduced use are safe and effective.