To gain valuable insights into the gene interaction and the complex regulation system involved in the development of insecticide resistance in mosquitoes Culex quinquefasciatus, we conducted a whole transcriptome analysis of Culex mosquitoes following permethrin selection. Gene expression profiles for the lower resistant parental mosquito strain HAmCq(G0) and their permethrin-selected high resistant offspring HAmCq(G8) were compared and a total of 367 and 3982 genes were found to be up- and down-regulated, respectively, in HAmCq(G8), indicating that multiple genes are involved in response to permethrin selection. However, a similar overall cumulative gene expression abundance was identified between up- and down-regulated genes in HAmCq(G8) mosquitoes following permethrin selection, suggesting a homeostatic response to insecticides through a balancing of the up- and down-regulation of the genes. While structural and/or cuticular structural functions were the only two enriched GO terms for down-regulated genes, the enriched GO terms obtained for the up-regulated genes occurred primarily among the catalytic and metabolic functions where they represented three functional categories: electron carrier activity, binding, and catalytic activity. Interestingly, the functional GO terms in these three functional categories were overwhelmingly overrepresented in P450s and proteases/serine proteases. The important role played by P450s in the development of insecticide resistance has been extensively studied but the function of proteases/serine proteases in resistance is less well understood. Hence, the characterization of the functions of these proteins, including their digestive, catalytic and proteinase activities; regulation of signaling transduction and protein trafficking, immunity and storage; and their precise function in the development of insecticide resistance in mosquitoes will provide new insights into how genes are interconnected and regulated in resistance.