In Israel, the head louse, Pediculus capitis, developed resistance to DDT through the extensive use of this insecticide until the 1980s. In 1991, permethrin was introduced for control of DDT resistant P. capitis in Israel, leading to control failure of this pyrethroid insecticide by 1994. Pyrethroid resistance of P. capitis in Israel extends to phenothrin, which has not been used for louse control. We identified a glutathione S-transferase(GST)-based mechanism of DDT resistance in the Israeli head lice. This GST mechanism occurred before 1989, while permethrin resistance in P. capitis developed after 1994, suggesting that the main GST resistance mechanism selected by DDT use does not confer any pyrethroid cross-resistance. Esterase activity levels were equivalent in pyrethroid resistant and susceptible P. capitis field-collected in Israel, and in a susceptible strain of P. humanus, the body louse, indicating no involvement of any esterase-based mechanism in resistance. A weak monooxygenase-based permethrin metabolism resistance mechanism was the only factor identified which could account for any of the observed pyrethroid resistance in P. capitis. However, the lack of synergism of phenothrin resistance by piperonyl butoxide suggests that a non-oxidative mechanism is also present in the resistant lice. Therefore it seems probable that pyrethroid resistance in Israeli P. capitis is due to a combination of nerve insensitivity (knockdown resistance or 'kdr') and monooxygenase resistance mechanisms.