Substantial progress has been made toward the identification of new chemical entities geared for the fight against malaria. Modifications of flawed drugs through modern insight, re-engineering molecules on the basis of proven pharmacophores, and capitalizing on the biological niches of the parasite have proven to be successful strategies in malaria drug discovery. Since the discovery of the antimalarial activity of artemisinin (ART) in China in the late 1960s, ART and its derivatives have emerged as the frontline drugs for the treatment of malaria. A significant advance was achieved when the carboxylic acid substituted analogue was found to exhibit high oral bioavailability and a moderate half-life after oral administration of a 50 mg/kg dose to rats. The early successes led to a full lead optimization campaign ultimately identifying the clinical candidate OZ277. Like the ART derivatives, OZ277 exhibited a rapid onset of action in vivo while maintaining activity against all asexual blood stages of the parasite.