The need to understand the genetic basis of drug resistance in human pathogens has never been greater. The global incidence of drug-resistant organisms, such as those that cause malaria, continues to rise, while the repertoire of effective, inexpensive drugs is declining. Genomic technologies, such as DNA microarrays and full-genome sequencing offer new hope in advancing our understanding of the underlying genetic processes that facilitate a resistance phenotype. Importantly, evidence that drug resistance in many organisms can be a multigene, complex phenomenon implies that unbiased, genome-wide scans of diversity will be required to fully understand the molecular mechanisms of both established and novel resistance traits. While the potential application of full-genome approaches for deciphering mechanisms of drug resistance has yet to be fully realized, this review evaluates drug resistance in human malaria parasites and discusses the exciting role genome-based systems could play in monitoring drug resistance, as well as guiding the implementation of efficient therapeutic strategies for malaria. The approaches reviewed within this article will be applicable to all known or emerging microbial pathogens.