A paper in this issue of Photochemistry and Photobiology by Cassidy et al. describes the use of a sophisticated drug delivery vehicle prepared by the hot melt extrusion process to deliver photosensitizers to the colon. The smart vehicle protects its cargo through the acidic environment of the stomach but releases the active photosensitizers in the higher pH and anaerobic environment of the colon. The goal is to use photodynamic therapy (PDT) to destroy pathogenic microorganisms that can cause disease when they grow out of control in the colon. Since the colon is an environment with a low oxygen concentration the investigators also used tetrachlorodecaoxide, an oxygen donor to boost the available oxygen concentration. The paper reports results with Enterococcus faecalis and Bacteroides fragilis but the real medical problem demanding to be solved is Clostridium difficile that can cause intractable drug-resistant infections after antibiotic use. There still remain barriers to implementing this strategy in vivo, including light delivery to the upper colon, oxygen availability and optimizing the selectivity of photosensitizers for bacteria over colon epithelial cells. Nevertheless, this highly innovative paper lays the ground for the study of an entirely new and significant application for antimicrobial PDT.