Melioidosis is a serious human infection caused by the environmental Gram-negative bacterium Burkholderia pseudomallei. Outcome following melioidosis remains poor despite 20 years of clinical research. Overall mortality is 50% in north-east Thailand (35% in children) and 19% in Australia. Relapse is common (13% over 10 years), and results from failure to eradicate the organism. Treatment is required to complete 12–20 weeks, or longer if clinically indicated. This is divided into intravenous and oral phases. Clinical trial evidence supports the use of ceftazidime or a carbapenem antibiotic for initial parenteral therapy, which should be administered for at least 10–14 days. This is followed by a prolonged course of oral antimicrobial therapy with trimethoprim–sulfamethoxazole (TMP–SMX) with or without doxycycline. Amoxicillin–clavulanate is an alternative for children, pregnant women and for patients with intolerance to first-line therapy. Resistance of B. pseudomallei to these drugs is rare, with the exception of TMP–SMX; resistance rates are approximately 2.5% in Australia and 13–16% in Thailand. There is a lack of evidence for the value of adjunctive therapies in the treatment of melioidosis. Future studies aim to address whether meropenem is superior to ceftazidime during parenteral therapy, and whether doxycycline is a necessary component of oral treatment.