Several lines of evidence indicate that mitochondria are an especially sensitive target for photodamage. Reports of cross resistance between photodynamic therapy (PDT) and the drug cisplatin, along with evidence that depletion of mitochondrial DNA (mtDNA) sensitized cells to cisplatin suggested a study of the photodynamic responsiveness of murine leukemia control L1210 cells versus cells depleted of mtDNA. Loss of mtDNA led to an increased sensitivity to mitochondrial photodamage, while the cytotoxic effects of lysosomal photodamage were not affected. Cells depleted of mtDNA showed an enhanced apoptotic response to PDT involving a mitochondrial target, compared with control cells.