A disadvantage of using target-based drug discovery in the search for new antimalarials is that predicting which targets will be essential for parasite growth in mammalian hosts is often difficult. In addition, well-validated targets may not yield new classes of compounds. Finally, resistance may emerge more quickly for compounds that interact with a single cellular target. Thus, recent drug screening efforts have shifted to cell-based assays, yielding thousands of potent antimalarial compounds. The challenge is now to discover the mechanism of action (MOA) of these compounds to facilitate medicinal chemistry. This review discusses the use of genome- or systems-based methods to characterize the MOA of such compounds.