Photodynamic therapy (PDT) is based on the combined administration of photosensitizing drugs and light to treat a variety of malignant, pre-malignant and also non-malignant diseases. The reactive species resulting from the excitation of the photosensitizers are at the origin of their photodegradation, which has an influence on the treatment outcome. PDT has a long history, including the improvements of photosensitizers and light delivery systems, which led to approved clinical applications. A knowledge of the photobleaching processes occurring during PDT will help implicit dosimetry, as it describes multiple photophysical, photochemical and photobiological factors involved in PDT. Due to this the clinical efficacy of PDT and optimisation of treatment regimes will be allowed. This article draws a light on key concepts like importance of photosensitizer photobleaching, the central role of light administration parameters (dosimetry, fluence, fluence rate, drug-light interval and light fractionation), and the critical role of oxygen to optimize the PDT treatment regimes for improved clinical efficacy. The main conclusions from this review work is that the efficiency of PDT can be, in certain cases, significantly enhanced by light fractionation; that most photobleaching processes involve singlet oxygen and obey second-order kinetics; and that the rate of photosensitizer photobleaching depends on initial drug concentration. This review also concludes that there is no straightforward approach to optimizing PDT given the complexity of the mechanisms involved, as well as the variety of diseases, organs, photosensitizers and PDT regimes that have been studied and reported.