Antimicrobials are an important source of hospital expenditure. Traditionally, severe bacterial infections have been treated initially with intravenous antibiotics, followed by physician-directed switch to oral therapy. Unfortunately this approach results in unnecessary prolongation of intravenous treatment, with all its inherent disadvantages. Sequential antibiotic therapy, however, ensures an early switch to the oral route when the patient is clinically stable. This increasingly employed strategy is safe and results in improved quality and cost-effectiveness of health care. To ensure timely and appropriate switch, such programmes need to be underpinned by clear guidelines and supported by a multidisciplinary team. In the future, key questions, such as what is the optimal time of switch for specific infections, and can conditions such as osteomyelitis and endocarditis be efficaciously treated with oral therapy, need to be answered. Only then will clinicians be able to practise evidence-based infection management incorporating sequential antimicrobial therapy.