Current evidence suggests that CDC25A is not only a major regulator of both G(1)/S and G(2)/M transition during unperturbed cell cycle progression, but also a critical checkpoint mediator. While CDC25A is overexpressed in a variety of human cancers, a key question remained unanswered whether such overexpression of this CDK-activating phosphatase was a mechanism or consequence of accelerated proliferation and other malignant phenotypes. Recent studies on the tumor suppressive roles of checkpoint proteins suggest that overriding checkpoint response leads normal or pre-cancerous cells to genomic instability and cumulative malignant changes. Here we provide our views on the role of CDC25A in cancer development and genomic stability, discussing insights from our recent studies on Cdc25A knockout mice and MMTV-CDC25A transgenic mice.