All photosensitizers applied in experimental and clinical photochemotherapy (PCT) of cancer are degraded during light exposure. Under certain conditions this may be a disadvantage since larger light fluences are needed to destroy the malignant tissue. However, photodegradation may also offer an advantage: if the applied dose of sensitizer is so low that most of it is photodegraded before normal tissue is destroyed, but still large enough to sensitize the tumor to destruction, one may achieve a larger tumor to normal tissue therapeutic ratio than when using a higher dose of sensitizer. Tumors usually contain two to ten times higher concentrations of sensitizers than do the surrounding normal tissues. We have studied the photodegradation of a number of sensitizers, including Photofrin (PII), benzoporphyrin derivative mono acid ring A (BPD), chlorin e6 (Chle6) 5-aminolevulinic acid (ALA)- induced protoporphyrin IX (PpIX), meso-tetrahydroxyphenyl-chlorin (m-THPC), meso- tetrahydroxyphenyl-porphyrin (m-THPP) tetraphenylporphine tetrasulfonated (TPPS4), aluminum phthalocyanine disulfonated (AlPcS2), tetrasulfonated (AlPcS4) and zinc phthalocyanine (ZnPc) in liposomes. The sensitizers were injected in Balb/c nude mice and exposed to light from an argon pumped dye laser, tuned to the appropriate therapeutic wavelength at a fluence rate of 100 mW/cm2. The sensitizer fluorescence in the laser- exposed skin was monitored by a fiberoptic probe coupled to a fluorescence spectrometer. The kinetics of the fluorescence decay during PCT were, in all cases, nonexponential but differed from dye to dye. Chle6 and m-THPC were found to be the most photolabile sensitizers. AlPcS4 and AlPcS2 and, to a minor degree, TPPS4 showed a peculiar fluorescence increase during PCT, similar to what we have found earlier for these sensitizers in cells in vitro. The fluorescence increase is indicative of lysosomal localization and perforation of the lysosomes during PCT.