The continued evolution of antimicrobial resistance in the hospital and more recently in the community threatens to seriously compromise our ability to treat serious infections. The major success of the seven-valent Streptococcus pneumoniae vaccine at reducing both infection and resistance has been followed by the emergence of previously minor serotypes that express multiresistance. The almost universal activity of cephalosporins and fluoroquinolones against community Escherichia coli strains has been compromised by the spread of CTX-M β-lactamase-producing, fluoroquinolone-resistant strains, and the emergence of community-onset methicillin-resistant Staphylococcus aureus, particularly in the United States, has forced us to re-think our empirical treatment guidelines for skin and soft-tissue infections. Finally, our most potent and reliable class of antibiotics, the carbapenems, is compromised by the growth, primarily in intensive care units, of multiresistant Klebsiella pneumoniae, Acinetobacter baumanni, and Pseudomonas aeruginosa. The lack of a robust pipeline of new agents, particularly against resistant Gram-negative bacteria, emphasizes the importance of optimizing our use of current antimicrobials and promoting strict adherence to established infection control practices.