Since 2001, 40 countries have officially adopted artemisininbased combination therapy for treating Plasmodium falciparum malaria [1]. Of these countries, 20 have adopted the combination of artemether and lumefantrine as their first-or second-line treatment. Artemisinin and its derivatives are the most potent and rapidly functioning antimalarial drugs; they reduce the infecting malaria parasite biomass to w1/10 000 per cycle [2]. Is artemisinin-resistant malaria out there? The existence of artemisinin resistance is a much-discussed issue; if it develops and spreads, resistance to artemisinin derivatives, currently the most essential antimalarial drugs, has the potential to be the most devastating event in the history of malaria control. Suspected clinical artemisinin resistance was reported in Thailand, India and Sierra Leone as early as the 1990s [3–5]. Isolated in vitro resistance has been reported in several countries, particularly in and around Southeast Asia, and artemisinin-resistant strains have been obtained in laboratories by intermittently exposing malaria parasites in culture to increasing drug concentrations [6]. However, the relevance of many studies reporting artemisinin resistance is questionable because they are limited to either clinical or in vitro data. Measuring the clinical impact of antimalarial drug resistance is difficult, and resistance might not be recognized until it is severe. This is partly because routine health-information systems grossly misjudge the magnitude of the problem [7]. Despite the fact that few regional drug-resistance meetings pass without at least one country reporting either in vitro or in vivo artemisinin resistance, there has been no convincing evidence so far. Why are the current data not convincing? There are several reasons why clinical failures or in vitro thresholds alone are not sufficient to prove artemisinin resistance. First, the drug has an extremely short half-life and, when given as a monotherapy, requires a minimum therapy duration of 6–7 days or combination with antimalarial drugs with longer half-lives that reliably eliminate the remaining parasites. However, artemisinin monotherapy is often administered for only 3–5 days, which inherently leads to high percentages of treatment failure, irrespective of drug resistance [8]. Treatment failure is also caused by poor-quality, underdosed or fake drugs [9]. It is also important to distinguish recrudescence from reinfection, preferably by eliminating any chance of infection during the observation period or, alternatively, by PCR. A clinical failure with artemisinin compounds is, therefore, not necessarily associated with artemisinin resistance. Second, pharmacokinetic studies of artemisinin derivatives are difficult and expensive and, therefore, are rarely carried out in the course of artemisinin trials, thereby ignoring the role of the host metabolism for clinical treatment success. Third, in vitro drug-sensitivity tests alone are of little help in finding artemisinin resistance because they would have to use artificially defined thresholds of resistance that might have little clinical relevance for this drug. Fourth, the genetic markers of artemisinin resistance are not sufficiently well defined and, therefore, PCR is of little help in detecting this resistance. So, if artemisinin resistance is out there, how can we find it? The problem is that the early stages of increasing drug tolerance are generally not reflected by an increase in clinical failures. Detecting artemisinin resistance will require relatively large sample sizes and an integrated in vivo and in vitro strategy (Box 1). Therefore, in vitro testing has a crucial role in detecting the early stages of resistance. The only reasonable approach is a careful analysis of clinical …