Circulating lymphocytes from human peripheral blood have been used for population monitoring to assess DNA damage in somatic cells. Methods have been developed for measuring heritable damage by investigating the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in T lymphocytes. The original method uses an autoradiographic technique to enumerate variants that lack functional HPRT and are, thus, able to enter S phase in the presence of the toxic purine analogue 6-thioguanine (6TG). A major disadvantage of this method is that the nature of the 6TG-resistant (6TGR) variants cannot be verified. The techniques for the in vitro clonal growth of T lymphocytes is developed, which have enabled a number of groups to investigate the potential of this system for human population monitoring. As a part of the development of the system of population monitoring, a study is undertaken of the experimental procedures that affect the performance of the assay. The chapter discusses the mutant frequency in a range of normal individuals, some at risk groups, and cancer-prone patients with DNA repair defects.