Simple SummaryGlioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols, all glioblastomas are eventually fatal. Photodynamic therapy (PDT) is a light-based treatment method, which offers delivery of anti-cancer treatment to focal areas, thereby limiting side effects. As PDT has become an attractive option to target glioblastoma cells, this review summarizes such experimental efforts. The aims of this review were to discuss both the potential and shortcomings of current PDT strategies, analyze the challenges which currently prevent PDT from being a viable treatment for GBM, and highlight novel investigations of this therapeutic option. The review concludes with a commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers and proposing solutions, this review provides a path for optimizing PDT as a revolutionary treatment for GBM.AbstractGlioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo–radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection. Prior PDT approaches in GBM have been predominantly based on 5-aminolevulinic acid (5-ALA), a systemically administered drug that is metabolized only in cancer cells, prompting the release of reactive oxygen species (ROS), inducing tumor cell death via apoptosis. Hence, this review sets out to provide an overview of current PDT strategies, specifically addressing both the potential and shortcomings of 5-ALA as the most implemented photosensitizer. Subsequently, the challenges that impede the clinical translation of PDT are thoroughly analyzed, considering relevant gaps in the current PDT literature, such as variable uptake of 5-ALA by tumor cells, insufficient tissue penetrance of visible light, and poor oxygen recovery in 5-ALA-based PDT. Finally, novel investigations with the potential to improve the clinical applicability of PDT are highlighted, including longitudinal PDT delivery, photoimmunotherapy, nanoparticle-linked photosensitizers, and near-infrared radiation. The review concludes with commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers to clinical translation of PDT and proposing solutions, this review provides a path for optimizing PDT as a paradigm-shifting treatment for GBM.