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This chapter examines the basic principles used to collect, detect, and track pathogenic microorganisms. How do clinical laboratories know what organisms to suspect in a given case? What tests will unequivocally identify the right pathogen? How are the real pathogens found among the normal flora? Finding the source of an outbreak is also critical. How do epidemiologists identify “patient zero” and recognize and contain emerging diseases? The task of controlling the spread of disease is daunting and ever changing because microorganisms continue to evolve. Known pathogens change, eluding eradication efforts by the immune system and antibiotics, while new pathogens keep emerging. The world is depending on the next generation of microbiologists to face the growing threat of these evolving microbes.