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The versatility of cytochrome P450 reductase (<i>CPR</i>) in transferring electrons to P450s from other closely related species has been extensively exploited, e.g., by using <i>An. gambiae CPR</i> (<i>AgCPR</i>), as a homologous surrogate, to validate the role of <i>An. funestus</i> P450s in insecticide resistance. However, genomic variation between the <i>AgCPR</i> and <i>An. funestus CPR</i> (<i>AfCPR</i>) suggests that the full metabolism spectrum of <i>An. funestus</i> P450s might be missed when using <i>AgCPR.</i> To test this hypothesis, we expressed <i>AgCPR</i> and <i>AfCPR</i> side-by-side with <i>CYP6P9a</i> and <i>CYP6P9b</i> and functionally validated their role in the detoxification of insecticides from five different classes. Major variations were observed within the FAD- and NADP-binding domains of <i>AgCPR</i> and <i>AfCPR</i>, e.g., the coordinates of the second FAD stacking residue <i>AfCPR</i>-Y⁴⁵⁶ differ from that of <i>AgCPR</i>-His⁴⁵⁶. While no significant differences were observed in the <i>cytochrome c</i> reductase activities, when co-expressed with their endogenous <i>AfCPR</i>, the P450s significantly metabolized higher amounts of permethrin and deltamethrin, with CYP6P9b-AfCPR membrane metabolizing α-cypermethrin as well. Only the CYP6P9a-AfCPR membrane significantly metabolized DDT (producing dicofol), bendiocarb, clothianidin, and chlorfenapyr (bioactivation into tralopyril). This demonstrates the broad substrate specificity of <i>An. funestus CYP6P9a/-b</i>, capturing their role in conferring cross-resistance towards unrelated insecticide classes, which can complicate resistance management.