Inhibition of DNA replication in eukaryotic cells was one of the earliest effects of radiation to be reported and quantitated. The elucidation of the mechanism of this inhibition has been the focus of research in several laboratories for four decades. A significant development in recent years is the recognition that the mechanism of this inhibition has both direct (cis -acting) and indirect (trans -acting) components (for a review, see 1 ). Whereas the direct component is thought to derive from radiation-induced DNA damage that alters chromatin structure and inhibits DNA replication in cis , the indirect component is attributed to the activation by DNA damage of regulatory processes that inhibit DNA replication in trans . The latter mechanism of inhibition is equivalent to the activation of a checkpoint in S-phase (2 –5 ).