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Addendum to: Lozovsky ER, Chookajorn T, Brown KM, Imwong M, Shaw PJ, Kamchonwongpaisan S, et al. Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc Natl Acad Sci USA 2009; 106:12025-30; PMID: 19587242; DOI: 10.1073/pnas.0905922106.Malaria is a major public health problem affecting 500 million people each year. Only few anti-malarial drugs are now available for fighting this deadly disease and their effectiveness is alarmingly dwindling because of the drug-resistant strains. Here we discuss recent findings on the evolutionary process behind the gain of a resistant gene. It was shown that for a protein to become resistant to an inhibitor, an intricate stepwise order of mutations must be followed. The projected evolutionary steps were compared with the field data, which reflects the natural history of drug resistant development.