Nonetheless, lower DV pH for CQR parasites appeared paradoxical, because simplistically it is predicted to concentrate more drug within the DV by weak base effects. It is difficult to future science group see how concentrating more drug at the site of action works to confer drug resistance, but as pointed out [6, 82] in hindsight the physiology is obvious when examined alongside the chemistry of the principle CQ target, FPIX released from Hb. As mentioned, iRBC parasites detoxify FPIX by crystallization to Hz. In aqueous solution, FPIX dimerizes to a µ-oxo dimer. FPIX has two propionic acid side chains, thus µ-oxo FPIX is a tetraprotic amphipathic weak acid with four equivalent titratable groups, and a pKa near DV pH [6, 82] . As pH is dropped even subtly (0.1-0.3 units), because the titration curve of FPIX dimer with four equivalent pKa is exceedingly steep (shown in [82] ), even low levels of soluble dimer convert to insoluble (aggregated) dimer over a very narrow pH range (<0.5 units [82] ). CQ and other drugs bind well to soluble FPIX but not to aggregates. In addition, acid aggregation of FPIX accelerates conversion to Hz (to which drugs also do not bind well). For these reasons, lowering DV pH by as little as 0.1 units is actually predicted to be a potent pathway to CQ resistance [6] . Ingeniously, CQR parasites titrate one drug target to lower levels, and also bias pHdependent FPIX chemistry. That is, even though at DV pH FPIX monomer is likely to be more abundant than µ-oxo dimer [26] , FPIX equilibria are pulled away from monomer by acid aggregation phenomena. As explained in the first section of this review, it is now known that this simple picture is a bit more complex, and also involves quinoline drug-specific effects (e.g., CQ vs QN) on monomer-dimer equilibria and drug-FPIX aqueous versus lipid partitioning [26, 27] . The overall point is that ion dependent CQ resistance DV biochemistry drives a number of chemical conversions that will act to disrupt quinoline drug-FPIX interactions in very potent ways. However, importantly, lower DV pH caused by CQ resistance-associated mutant PfCRT that correlates with a VPL reversible CQR phenotype can only be one aspect of the CQ resistance mechanism and cannot explain all quinoline drug resistance. For example, evidence suggests lower DV pH may not be directly related to QN resistance, and might even be related to MQ hypersensitivity in some cases [56, 57] . As described earlier, added effects of proteins encoded by other identified loci (PfMDR, PfNHE) may hold clues to this complex spectrum of multidrug resistance phenomena. In addition, better definition of the molecular origins and repercussions of this altered pH is required. How does it occur? Is PfCRT a H + -coupled metabolite transporter that when mutated to a CQR form becomes partially uncoupled? Does PfCRT interact with the DV H + ATPase? Does PfCRT transport a counterion (i.e., Cl -) to shunt membrane potential in the presence of a high change in pH, such that CQ resistance mutations alter anion flux to indirectly cause a greater pH change? Do PfCRT CQ resistance mutations change substrate specificities for a facilitative diffusion transporter? These questions all have very different predicted consequences.