Regulated initiation of DNA replication relies on the firing of initiator proteins that bind specifically to origin DNA. The discovery of the first eukaryotic initiator, the Saccharomyces cerevisiae Origin Recognition Complex (ORC) has allowed us to discern some aspects of how the onset of replication is regulated. However, understanding the specifics of replication in metazoan organisms can only be achieved by directly addressing these questions in animal cells. This review deals with the current state of knowledge on the metazoan Origin Recognition Complex, its composition and regulation in higher eukaryotes, its role in the initiation of replication and beyond replication, and its possible connection with human pathology.