The toxicity and metabolism of the photoisomers of aldrin, isodrin, heptachlor, and dieldrin, i.e., respectively, photoaldrin, photoisodrin, photoheptachlor, and photodieldrin, in Musca domestica L., have been investigated. To a susceptible strain of flies, all photoisomers with the exception of photoisodrin were more toxic and acted more rapidly than their parent compounds. Pretreatment with 2.5 µg sesamex per fly synergized isodrin, photoisodrin, and photoheptachlor but antagonized aldrin and heptachlor. Greater amounts of sesamex were necessary to synergize photodieldrin, photoaldrin, and dieldrin. To a multiresistant strain, sesamex synergized photoisodrin, but was antagonistic to photodieldrin, photoaldrin, and photoheptachlor. Based on the recoveries of insecticides applied externally, the increased toxicity of certain photoisomers and their synergism by sesamex was not due to more rapid penetration. The synergism by sesamex of isodrin and photoisodrin, the latter of which is incapable of epoxidation and oxidative dehydrochlorination to a ketone, appeared to be related to the inhibition of its detoxication by a system which can be stimulated by phenobarbital. In the resistant strain, sesamex inhibited the metabolism of aldrin, photodieldrin, and photoaldrin, in the case of the latter 2 compounds to the ketone of photodieldrin (Klein’s Metabolite). This inhibition lowered the toxicities of these compounds, showing that the ketone formation enhanced their toxicity to house flies. Photoaldrin was epoxidized in vitro by the same microsomal system responsible for aldrin epoxidation. The latter process was inhibited by photoheptachlor, which is incapable of epoxidation but may be oxidatively dehydrochlorinated at such microsomal sites.