The effectiveness of photodynamic therapy (PDT) for treating solid tumors remains variable. Our research team has examined cellular and tissue responses associated with the use of PDT and we have observed increased expression of several prosurvival molecules that can modulate treatment efficacy. Specifically, angiogenic growth factors, inflammatory proteins, and anti-apoptotic molecules are often overexpressed following PDT-mediated oxidative stress. The relevance of PDT-induced expression of vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), matrix metalloproteinases (MMPs), and survivin will be reviewed. In addition, our team has had a long-standing interest in the application of PDT to treat retinoblastoma (Rb), an intraocular pediatric eye tumor. We describe our initial preclinical and clinical ocular studies as well as our recent cellular and tissue responses to PDT in Rb cells and tumors. These data provide new information on possible reasons why earlier PDT procedures were only partially effective in treating Rb. We conclude with suggestions on how combined modality approaches using targeted therapy together with fractionated PDT may enhance outcomes for treated ocular tumors.