Cross-resistance to (1R)- trans-permethrin (12-fold at LC50) and to (1R)-cis-permethrin (18-fold) was induced in Anopheles stephensi larvae by selection in the laboratory with DDT for 6 generations to a level of 144-fold DDT-resistance. Selection by (1R)-trans-permethrin of a sub-strain in F4 and F5 increased resistance to (1R)-trans-permethrin and (1R)-cis-permethrin to 15-fold and 20-fold the initial levels, respectively. The highest cross-resistance to (1R)-trans-permethrin (19-fold) and to (1R)-cis-permethrin (23-fold) were detected in a substrain that had been selected in F4 and F5 by DDT in combination with the synergists DMC and piperonyl butoxide. In none of the selected strains were DDT or pyrethroids synergized significantly by these metabolic inhibitors thus suggesting reduced sensitivity of active site as the major factor responsible for the observed resistance. Intracellular recordings from larval muscles of susceptible and resistant strains revealed that the concentrations of (1R)-cis-permethrin needed to cause an increase in miniature excitatory postsynaptic potentials were 5 X 10-11M and 1 X 10-9M, respectively. Miniature excitatory postsynaptic potential frequency is a measure of the poisoning of motor nerve terminals, these being particularly susceptible to pyrethroid and DDT poisoning. Thus, the observed resistance appears to be due largely to change(s) in the nervous system of resistant strains, producing a lower sensitivity to the toxic action of permethrin.