It is now clear that there are multiple molecular layers to multidrug resistance pathways and that these continue to evolve. Elucidating the molecular function of proteins that appear to be membrane transporters and that are mutated in CQR malarial parasites (which are often also MDR) remains a critical area of study and is briefly summarized in the last section of this review. future science group Initial genetic studies: cg2 versus Na + /H + exchange; the wrong gene but the correct physiology A genetic definition of CQ resistance began with the cloning of pfcg2 [45] , a technical tour de force essentially started years earlier via the successful creation of CQS × CQR cross progeny [46] . Correlation between specific pfcg2 sequence and CQS or CQR status was found for all but one strain of P. falciparum examined. The one exception, strain Sudan 106/1, turned out to have a special utility in characterizing the true CQ resistance determinant (see later section on PfCRT). Prior to that work, Lanzer et al. concluded that mutated PfCG2 protein was a dysregulated Na + /H + exchanger (NHE) that also pumped CQ out of the cell [47, 48] . Wellems et al. questioned this because subcellular localization revealed PfCG2 in vesicle-like structures near the parasitophorous vacuolar space and the DV [49, 50] , not within the plasma membrane as envisioned by Lanzer et al [47] . Follow-up studies by Bray and Ward did not measure any Na + dependency for CQ resistance, arguing against a strong role for NHE in influencing CQ transport or any other feature of CQ resistance [51] . Most recently, quantitative trait loci (QTL) analysis, availability of the P. falciparum genome and novel single-cell imaging in an extensive series of drug-resistant progeny suggested that altered NHE and cytosolic pH (pH cyt ) are indeed related to resistance, but that the relevant ion exchanger is not PfCG2 (see later section on P. falciparum Na + /H + exchanger [PfNHE]), and that resistance to QN is more influenced by these changes than CQ resistance [52] .