Although infection prevention traditionally has approached the problem of resistance primarily from the aspect of preventing transmission from an infected patient to a noninfected patient, more needs to be done to improve how antimicrobials are commonly used. Antimicrobial use is the main selective pressure responsible for the increasing resistance seen in hospitals. Patients come to possess a resistant pathogen either by transmitting bacteria that already have the resistance gene in place or by having their bacteria acquire a gene that codes for resistance. The former is more common because it merely requires a handshake while the latter takes days to weeks to develop. To have an impact on antimicrobial use so as to reduce resistance, infection preventionists (IPs) need a working knowledge of available antimicrobials, principles for their appropriate use, the mechanisms by which these drugs inhibit microbial growth, and the mechanisms by which microorganisms develop resistance. In addition, IPs need to understand promising new strategies to improve antimicrobial use and how members of the infection prevention community can become more involved.