Abstract: The susceptibility of Culex pipiens collected from different localities of the Sharkia Governorate, Egypt, to malathion and lambda-cyhalothrin was investigated for 11 successive generations. Larval Cx. pipiens developed 57 and 305-fold resistance to malathion and lambda-cyhalothrin, respectively after 11 successive generations of selection pressure. The susceptibility of unselected generations, due to non-exposure to both insecticides for 11 generations, was increased to 1.1-fold in F11 for malathion and to 1.5-fold in F11 for lambda-cyhalothrin. Acetylcholinestrase (AChE) activity increased gradually in both selected and unselected generations until the 11th generation. The activity of AChE in generations (F1-F7) selected with malathion was significantly lower than that of the lambda-cyhalothrin selected and unselected generations. General esterase activity increased 3.7 and 3.0-fold (malathion) and 4.2 and 3.6-fold (lambda-cyhalothrin) compared with the susceptible strain (LS-CP), when either α-napthyl acetate (NA) or β-NA were used as general substrates in F11 selected generations, respectively. A significant increase in glutathione-S-transferase (GST) activity was noticed in the F11 generation recording 6400 and 8800 μmoL min-1 mg-1 protein for malathion-and lambda-cyhalothrin-selected generations, respectively. The ratios recorded in the 11th generations were 3.6 and 4.9 fold as compared with LS-CP for malathion and lambda-cyhalothrin selected generations, respectively. Our results indicate that the Cx. pipiens mosquito strain from Egypt can increase resistance to malathion and lambda-cyhalothrin if these insecticides are continuously or rotationally used to control this species. Increased resistance is likely to be associated with increased activity of target and metabolic enzyme systems.