The heterogeneous nature of cancer is promoted by elevated levels of aneuploidy caused by genomic instability (GIN), which predisposes cells to malignant transformation. Cep55, a protein initially characterized by our laboratory as a cytokinesis regulator has also been shown to be an important regulator of GIN, and its overexpression correlates with aggressiveness, metastasis and poor prognosis in many tumor types. Moreover, our lab recently showed that loss of CEP55 sensitizes cancer cells to anti-mitotic agents, which could be a potential therapeutic strategy against CEP55-overexpressing tumors. The perturbation of Cep55 levels in vitro studies has also highlighted its roles in PI3K/AKT regulation, midbody fate, and stemness. To better understand the role of Cep55 in the cancer context, we generated the first Cep55 Knockout (KO) mouse model. To determine if Cep55 loss would perturb transformation ability, we transformed Cep55+/+ and Cep55-/- MEFs with E1A/Ras oncogenes. Strikingly, we found that anchorage‐independent colony formation was reduced upon E1A/Ras Cep55-/- in colony formation assay and 3D culture. Similarly, loss of Cep55 abrogated and delayed tumor formation in NOD/SCID mice injected intraperitoneally with E1A/Ras-transformed Cep55-/- MEFs. To validate these effects in a proper preclinical gene-therapy model, we utilized Ptenfl/fl,Rosa26 Cre ERT(2) (hyperactive-AKT signaling) and Kras LSL G12D (hyperactive MAPK/ERK signaling) tumor-prone models to establish a hybrid line with inducible Cep55 KO to investigate the consequences of Cep55 loss in tumor formation in these mice. The data confirm that loss of Cep55 delayed Pten-deficient malignancies and increased overall survival in Pten-deficient mice. Moreover, in a lung-specific Kras LSL G12D mouse model, loss of Cep55 decreased tumor burden. These data highlight a broader role of Cep55 in contributing to tumorigenesis in these mouse models. Altogether, our data suggest that Cep55 may be a valuable molecular target to prevent the initiation and progression of cancer.