Significant increases in prevalence of resistance to antibiotics have been observed in common pathogens of humans in the United States and worldwide. The consequences of the appearance and spread of antibiotic resistance have included increasing morbidity, mortality, and cost of health care. The fundamental cause for the appearance and spread of antimicrobial resistance has been increasing antimicrobial use. However, other factors contribute in both inpatient and outpatient settings. Recognizing the important causes of increasing antibiotic resistance in these settings has led to practical recommendations, which health care facilities and outpatient practitioners will need to review, adapt, and apply for maximum local effectiveness for progress to be made in addressing one of the most challenging problems facing modern medicine.