Objective: This paper reviews the development and clinical validation of photodynamic diagnosis (PDD) of bladder cancer. Methods: The authors reviewed the literature on the development of PDD, in particular the evidence for the clinical efficacy of hexaminolevulinate PDD in the diagnosis of bladder cancer. Results: After initial work on ultraviolet cystoscopy following oral tetracycline, the focus of PDD research shifted to the use of synthetic porphyrins. First, the prodrug delta-aminolevulinic acid (ALA) was shown to cause a transient but significant accumulation of protoporphyrin IX (PpIX) in malignant or premalignant bladder tissue. Excitation by blue light leads to PpIX fluorescence (red), which distinguishes tumour from normal tissue (blue). Hexaminolevulinate (HAL, Hexvix), an ester of ALA, was then developed and has greater bioavailability and stability than the parent compound. It has been approved for clinical use in the diagnosis of bladder cancer. Clinical studies have shown that HAL PDD detects tumours, including carcinoma in situ (CIS), that are missed by conventional white-light cystoscopy. Conclusions: HAL PDD is a valuable aid to the detection of bladder tumours, including CIS. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.