Maintenance of genomic integrity is paramount to cell survival. Precise duplication of our genome and appropriate cellular response to genotoxic stress is critical to maintain genome stability. Origin Recognition Complex (ORC) and ORC-Associated (ORCA) are required for the initiation of DNA replication and regulate heterochromatin organization. ORC and other human replication initiation proteins are required for replication of Epstein Barr virus (EBV) that is associated with Burkitt’s lymphoma. My laboratory identified ORCA/LRWD1, that maps to 7q22.1 in human cells, a region frequently amplified in esophageal squamous cell carcinoma or shows rearrangements and loss of heterozygosity in myelodysplasia and acute leukemia. Recent study has shown its involvement in Ewing’s sarcoma. Multiple subcomplexes of ORC regulate different aspects of cell cycle progression and thus play pivotal roles in the maintenance of genomic stability. The long-term goal of my laboratory is to understand how ORC executes and coordinates various aspects of cell growth, proliferation and survival. Several replication initiation proteins including MCMs are used widely for cancer diagnostic purposes. Understanding how replication proteins govern multiple cellular pathways is expected to uncover novel pathways that would be useful to prevent tumorigenesis and key to allow more effective therapeutic targeting to combat cancer.