Coffee can exert in vitro and ex vivo antimicrobial activity against several bacteria and fungi which are relevant for food safety and human health, including oral diseases. Coffee's antimicrobial activity can be attributed to several individual compounds, among them naturally occurring coffee compounds and those resulting from the roasting process. However, it is more likely that the antimicrobial activity results from the simultaneous action of various compounds. Some probable mechanisms for the antimicrobial activity are presented in this chapter but the exact mechanism remains to be elucidated. Roasted, but not green, coffee shows antimicrobial activity. The degree of roasting and coffee concentration affect the intensity and spectrum of antimicrobial activity; whereas the influence of other variables needs elucidation. Antimicrobial activity has also been found in coffee by-products with potential use in different applications and will be explored.