BACKGROUND: Pyrethroid resistance has been well documented in Anopheles arabiensis, one of the major African malaria vectors, and the predominant malaria vector in South Africa. METHODS: In this study, the genetic basis of pyrethroid resistance in a selected laboratory strain of An. arabiensis from South Africa was investigated using a custom-made microarray, known as the An. gambiae detoxification chip. RESULTS: A large number of P450 genes were over-transcribed, as well as a suite of redox genes and glutathione S-transferases. The five genes that showed the highest level of gene transcription when compared with an insecticide susceptible strain were: CYP6AG2, CYPZ1, TPX2, CYPZ2 and CYP6P1. CONCLUSIONS: Permethrin resistance in South African An. arabiensis is associated with increased transcription of multiple genes, and a large proportion of these genes were also previously recorded as over-transcribed in another An. arabiensis strain selected for resistance to DDT with cross-resistance to deltamethrin. The deltamethrin resistance developed de novo in the DDT-selected strain and is most likely due to increased transcription of those genes associated with DDT resistance. However, of particular interest was the fact that the strain selected for resistance to pyrethroids did not develop de novo resistance to DDT. These differences are compared and discussed. ; National Research Foundation Scarce Skills Scholarships and DAAD (LN), National Research Foundation and the National Health Laboratory Service-Research Trust to LLK, partial funding from the Department of Science and Technology, National Research Foundation Research Chair Initiative grant to Maureen Coetzee. ; http://www.parasitesandvectors.com/content/6/1/229 ; am2014