Photodynamic therapy (PDT) is a treatment that combines a photosensitizer with light to generate oxygen-dependent photochemical destruction of diseased tissue. This modality has been approved worldwide since 1993 for the treatment of several oncological and nononcological disorders. PDT continues to be interested in both preclinical and clinical research, with more than 500 publications each year during the past 5 years. This minireview focuses on the effects of PDT on tumor stroma. A tumor consists of two fundamental elements: parenchyma (neoplastic cells) and stroma. The stroma is composed of vasculature, cellular components, and intercellular matrix and is necessary for tumor growth. All the stromal components can be targeted by PDT. Although the exact mechanism of PDT is unknown, emerging evidence has indicated that effective PDT of tumor requires destruction of both parenchyma and stroma. Further, damage to subendothelial zone of vasculature, in addition to endothelium, also appears to be a crucial factor. The PDT-generated immune response as a way of vaccination for treatment and prevention of metastatic tumors remains to be exploited.