Abstract Persistent luminescence (PerL) materials continue emitting light long after their excitation has stopped. Prepared in the form of nanoparticles they revealed their full potential as bio-nanoprobes for in vivo small animal imaging in the last 15 years. PerL materials enable to overcome the limitation of weak light penetration in living tissues. As such, they constitute remarkable light mediators to implement photodynamic therapy (PDT) in deep-seated tissues. This article reviews the recent achievements in PerL-mediated PDT in vitro as well as in small animal cancer models in vivo . PerL-mediated PDT is realized through the smart choice of a tandem of a PerL material and a photosensitizer (PS). The physical association of the PerL material and the PS as well as their targeting ability is debated. Implants or mesoporous nanoparticles emerge as particularly valuable cargos that further permit multimodality in imaging or therapy. The diversity of charge-trapping mechanisms in a few PerL materials enables a large versatility in the excitation protocols. Although the PerL agent can be pre-excited by UV light before its introduction into the animal, it also induces effective PDT after simple infrared or visible LED illumination across tissues as well as after a mild X-ray irradiation.