The transcriptional regulation of gene expression is a primary means by which insects adapt to a changing environment. The evolution of insecticide resistance is conferred through mechanisms, typically requiring the interaction of multiple genes. Consequently, the characterization of gene regulation and interactions in resistance is fundamental for achieving an understanding of the complex processes responsible for resistance. cDNA macroarray technology offers a promising new approach for investigating the complicated processes responsible for resistance development by revealing the interrelations of all of the elements in a resistant system simultaneously. In the current study, we compared the gene expression profiles of resistant and susceptible Culex quinquefasciatus mosquitoes, using a combination of subtractive PCR hybridization and cDNA microarray technique. By screening of 1500 cDNA clones from a resistant-susceptible mosquito subtractive library, we identified a set of genes with up-regulated expression in insecticide resistant Culex mosquitoes through transcriptional profiling compared to those in susceptible mosquitoes. These genes are vital for cellular and molecular metabolism, signal transduction, vesicular and molecular transport, protein biosynthesis, ubiquitination, and neuronal survival, but most have not previously been implicated in insecticide resistance. Functional studies of resistance-associated up-regulated genes should shed new light on both the molecular basis of resistance and the regulatory pathways that lead to it.