Photodynamic therapy (PDT), in which stained cells are damaged by light in the presence of oxygen, is now widely used for tumor destruction. Photogenerated singlet oxygen and reactive oxygen species cause oxidative stress and cell death. The potential ROS sensors and following intracellular processes leading to cell death are considered. The cell death mode (necrosis or apoptosis) is shown to be controlled not only by PDT parameters (irradiation intensity, intracellular photosensitizer localization and its concentration) but also by signal transduction processes. Calcium and adenylate cyclase signaling pathways, receptor tyrosine kinases, MAP kinases, phosphatidylinositol 3-kinase pathway, various protein kinases and phosphatases, transcription factors, ceramide, NO, the plasma membrane, mitochondria and endoplasmic reticulum are involved in the cell response to photodynamic injury and following death. Combination of PDT and pharmacological modulators of signaling pathways can either enhance injury of malignant cells, or protect surrounding normal cells.