Bacteria have shown a remarkable ability to develop resistance to antibiotics, which pose both therapeutic problems for physicians and diagnostic problems for microbiologists. I will focus this lecture on three separate, all-too-common problem organisms – methicillin-resistant Staphylococcus aureus, multidrug-resistant Acinetobacter baumannii, and carbapenemase-resistant gram-negative rods. The successful control of these organisms in a hospital setting requires a comprehensive screening program combined with a rigorous infection control program. Without both programs any diagnostic or epidemiologic efforts will be wasted. I will illustrate the challenges in developing screening tests with MRSA testing, as well as the consequences of not controlling highly virulent organisms with the description of outbreaks caused by drug-resistant Acinetobacter and Klebsiella.