Since the early 1990s, photodynamic therapy (PDT) has been clinically used as a therapeutic approach to ablate pathogenic and malignant cells in various diseases, from bacterial infections to cancer. PDT combines light, oxygen and photosensitizers to produce toxic reactive oxygen species locally, and cause cell death. A broad range of chemical architectures have been reported as effective PDT agents, including organic and inorganic molecules, superoxide radical generators, core-shell metal nanoparticles, metal-organic frameworks and mesoporous organosilica nanoparticles. Recently, the groups of Gasser, Chao and Sadler described the use of highly oxidative iridium photocatalysts to induce intracellular redox imbalance and kill cancer cells even in the presence of low concentrations of oxygen. In addition to exhibiting high phototoxic potential, a critical requirement for PDT agents is to exhibit toxicity only in target cells so that therapeutic benefit can be achieved with tolerable light doses and minimal side effects in healthy tissues. Different strategies have been described to fine-tune the structures of photosensitizers and enhance their cell selectivity. Activatable agents exploit some of the biochemical features of tumors (e.g., low pH, glutathione, proteases) to release photosensitizers in cancerous tissues, showing promise in reducing bystander toxicity. Alternatively, photosensitizers can be conjugated to antibodies, which favor accumulation in tissues that express specific cell-surface markers. Whereas these approaches can be effective in the presence of abundant biomarkers, they show limitations at early stages of disease when the biochemical and proteomic signatures of target cells are not dissimilar to those of surrounding healthy tissues (e.g., microtumors). New chemical designs to directly deliver photosensitizers to individual pathogenic and malignant cells under in vivo physiological conditions would significantly extend the clinical applications of PDT.