More recent studies with PQ have developed compelling evidence that the metabolism to its active metabolites is dependent on the activity of cytochrome P450 2D6 (CYP2D6) [7, 17]. This evidence is based on the failure of PQ therapy in CYP2D6-null metabolizers and the ablation of the anti-malarial effect of PQ in CYP2D knockout mice. Thus, it would naturally be expected that inhibition of CYP2D6 would impair the efficacy of PQ. However, both QN and CQ have been shown to be moderate inhibitors of CYP2D6 with significant effects at clinically used doses [18, 19]. It is puzzling then, that they do not effectively antagonize the anti-malarial effects of PQ, and rather are potentiators. This suggests that either the putative dependence of PQ efficacy on CYP2D6 is incorrect, or that CQ and QN may be acting by other mechanisms.