Regulation of mammalian mtDNA replication most likely involves molecular events surrounding initiation of leading-strand DNA synthesis at the D loop. As outlined earlier, OL is well separated physically in the genome, and there is no evidence to indicate that a round of productive replication can begin there. Our knowledge of the exact characteristics of the DNA primase activity that recognizes 0, has not advanced beyond work described in an earlier review. This is due, at least in part, to the very low abundance of this activity in the cell. However, we can describe some of the fundamental aspects of initiation of leadingstrand synthesis that enable, in turn, some predictions on how regulation of replication may occur