Different molecular models for how CQ inhibits Hz formation have been proposed, including the lysosomotrophic model wherein changes in DV pH caused by CQ diffusion titrate either Hb digestion, FPIX derivatization, Hz crystallization, or some combination. Alternatively, CQ might inhibit a heme/enzyme complex that forms as an intermediate. However, most evidence suggests that CQ and other anti malarials bind directly to one or more chemical forms (monomers, dimers) of FPIX [5, 6, 14, [16] [17] [18] [19] [20] . These data suggest that quinolines directly inhibit Hz formation by sequestering one or more precursors of the crystal unit, or perhaps by interacting with growing faces of the Hz crystal [17] . It then follows that the CQ resistance mechanism involves the disruption of one or more of these CQ-FPIX interactions. Importantly, since FPIX is made by the host (not the parasite), the target cannot be mutated, and since its release is an inevitable consequence of essential Hb digestion its availability cannot be reduced. Thus two of the most common routes to drug resistance are eliminated (e.g., mutation or decreased expression of target). To become CQR the parasite must therefore either compartmentalize the drug in a different way, alter signal transduction related to death or modify the target in some biochemically unique way. Indeed, Bray et al. extrapolated CQ-binding data and determined that intracellular target affinity differs for CQS versus CQR parasites [9] , so some biochemical transformation of FPIX for CQR versus CQS parasites seems probable. Another study demonstrated this directly in vivo [17] . Recently, we have been the first to determine the atomic-level structures of noncovalent CQ, quinine (QN), future science group amodiaquine (AQ) and quinidine (QD)-µ-oxo dimer FPIX complexes [18, 19] and these structures reveal a number of routes for altering FPIX-drug interactions. Remarkably, we have also discovered that when CQ and FPIX are added together under conditions that mimic that of the DV, a covalent (dative Fe-quinolinal N) FPIX-CQ complex is formed [20] . These discoveries enhance our understanding of how drugs inhibit Hz crystallization, and define important molecular features of CQR malaria. That is, noting the presence of at least two different CQ-FPIX complexes, two different FPIX dimers and the different pH dependencies for complex and dimer formation, we learn that there are several quite simple routes that the parasite can take to titrate multiple drugheme target interactions. Indeed, slightly altered DV pH, volume, ionic or lipid composition for CQR versus CQS parasites [21, 22] can easily alter the ratio of monomeric versus dimeric FPIX, the ratio of µ -oxo versus head to tail dimer, or ratios of multiple drug-heme complexes. Since even closely related quinoline antimalarials have different preferences and affinities for various chemical forms of FPIX, these data suggest that heme target-affinity differences for CQR parasites seen in vivo are easily explained via alterations in physiologic parameters (DV pH, volume, ionic and lipid composition and so on) known to exert enormous influence on Hz and drug-heme chemistry [23] .