The use of antibiotic prophylaxis has long been established to prevent the development of invasive infections. In many settings, it is currently considered to be the standard of care to administer antibiotics prior to surgical procedures. The aim is to decrease the load of organisms at the site of manipulation and therefore minimize the appearance of local as well as distant infection. With the increasing number of antimicrobial agents available on the market, physicians are often faced with a dilemma when trying to decide which agent to use. This review addresses the current recommendations of antimicrobial prophylaxis in surgical procedures, in the prevention of infective endocarditis, as well as the prophylaxis required following exposure to highly infective bacteria.