The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Medline 1966 to 2005 was searched using approximately 200 different medical subject heading terms (e.g. alternative medicine) and free text words (e.g. laetrile). Prospective clinical trials of unconventional treatments in cancer patients were sought, excluding studies with only symptom control or non-clinical (e.g. immune) endpoints. Trial data were extracted by two reviewers using a standardised protocol. A total of 14 735 articles were identified, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data.