To analyze the available literature describing the treatment of relapsed aggressive non-Hodgkin's lymphoma (NHL) with single-agent chemotherapies, several comprehensive electronic and manual inspections of the literature were performed for the period from 1966 to the present. Each paper was examined to capture the following data: study type; patient demographics and characteristics; study endpoints, including responses, and method used to evaluate response; toxicities, and the power of the study. A wide variety of single-agent protocols continue to be studied, indicating no currently accepted standard therapy in this patient population. Reported response rates varied between 0 and 67%. The majority of trials were small, uncontrolled studies that used widely varying inclusion/exclusion criteria and had limited reporting of histology, response, prior treatments, and other key parameters. We were able to find only four agents, etoposide, vincristine, vinorelbine and possibly rituximab, with sufficient reproducible evidence to suggest greater than 30% activity (CR + PR rate) when given to patients with second or greater relapse of aggressive NHL. Consequently, the usefulness of the agents in these reports remains to be established in larger trials with more detailed reporting. The advantages that would be brought by an active non-myelosuppressive agent for patients having this condition emerge clearly from this review.