Prior to the availability of the P. falciparum genome, Ginsburg et al. quite logically suggested a plasma-membrane NHE must exist to decrease cytosolic acid caused by anaerobic glycolysis [77] . As mentioned earlier, Lanzer et al. suggested that pfcg2 found close to pfcrt on chromosome 7 encoded this NHE [48] , but this was disputed, since PfCG2 is actually peri-vacuolar [50] , not plasma membrane localized, and because the putative PfCG2-NHE homology was based on sequence ana lysis that did not account for very high AT content in malarial genes [49] . Regardless, the field has come full circle and the initial conclusions by Lanzer et al. were indeed partly correct (the physiology was correct, but not the genetic explanation). In our hands single-cell photometry (SCP) analysis of pH cyt for intra-erythrocytic parasites under continuous physiologic perfusion indeed show elevated pH cyt for some CQR parasites, but not all [54, 55, 57] . A corollary we suggested is that the relative size of the net cytosolic-DV pH gradient might be a more important parameter for CQ resistance versus QN resistance, rather than steady-state pH cyt or digestive vacuolar pH values alone [54] . Overall, a range of pH phenomena and genetic changes consistent with changes in pH regulation are associated with QN resistance and CQ resistance. As described [52] , we recently optimized localization of the pH probe BCECF exclusively to the parasite cytosol to avoid complexities in interpretation from earlier studies, and showed that elevated pH cyt is well correlated with QN resistance and increased apparent PfNHE activity [60] . We now believe there are at least two physiological signatures for QN resistance that segregate with the two genetic descriptions, and that one is alkaline pH cyt [52] . Technical details of PfNHE measurements have recently been questioned [78] , but these issues have hopefully been clarified [79] .