Recently, several studies have reported the detection of DNA from simian virus 40 (SV40), a macaque polyomavirus, in tumor tissues obtained from non-Hodgkin lymphoma (NHL) patients. SV40 accidentally contaminated poliovirus vaccines administered to millions of individuals in 1955-1962. A link between SV40 and NHL is biologically plausible because SV40 causes hematological malignancies in laboratory rodents. However, detection of SV40 DNA in human NHL tumors has not been confirmed by other laboratories. Casting doubt on an association between SV40 and NHL, follow-up studies of recipients of SV40-contaminated poliovirus vaccines have not revealed these individuals to be at increased risk of NHL. Furthermore, 2 recent case-control studies of NHL documented only infrequent SV40 antibody reactivity among NHL cases, and the prevalence of SV40 antibodies was similar in cases and controls. This review summarizes recent laboratory and epidemiological studies bearing on the question of whether SV40 is a cause of NHL in humans. The strengths and weaknesses of these data are discussed, and a framework for considering the collected evidence is presented. Many of the considerations raised in this review apply to the evaluation of data regarding other cancers, such as mesothelioma, brain tumors, and various sarcomas, for which an etiologic link with SV40 also has been proposed.