The expression of Skp2, the ubiquitin ligase subunit that targets p27Kip1 for degradation, is commonly overexpressed in human cancers. p27Kip1 is a negative regulator of the cell cycle that plays an important role in tumor suppression. Loss of p27Kip1 secondary to enhanced ubiquitin-mediated degradation results in uncontrolled proliferation and promotes tumor progression. In the present study the prognostic implications of Skp2 are reviewed and the mechanisms that regulate its expression in different human cancers. A review and analysis of the English literature was undertaken. Overexpression of Skp2 mRNA and protein levels was observed in many aggressive cancers and was commonly associated with down-regulation of p27Kip1 levels and loss of tumor differentiation. Skp2 is an independent prognostic marker for disease-free and overall survival and may provide additional predictive information to that provided by p27Kip1 alone. Targeting Skp2 in experimental models resulted in up-regulation of p27Kip1 and arrested cellular proliferation. Alterations in Skp2 expression have profound effects on cancer progression and may serve as an accurate and independent prognostic marker. Thus, determination of levels of Skp2 and p27Kip1 by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy. Skp2 may be an attractive target for the development of novel interventional therapy. Cancer 2008. © 2008 American Cancer Society.