Centromere dysfunctions leading to numerical chromosome alterations are believed to be closely related to human cancers. As a centromere-specific protein, centromere protein A (CENP-A) replaces the histone H3 in centromeres and is therefore considered a key factor of centromere identity. Researches have shown that CENP-A is overexpressed in many types of human cancers. However, the behavior and function of CENP-A in tumorigenesis have not yet been systematically summarized. In this article, we describe the pleiotropic roles of CENP-A in human cells. Moreover, we provide a comprehensive review of the current knowledge on the relationship between aberrant expression and ectopic localization of CENP-A and tumorigenesis, and the mechanism of the ectopic deposition of CENP-A in cancers. Furthermore, we note that some oncogenic viruses can modulate the expression and localization of this centromere protein along with its chaperone. At last, we also discuss the therapeutic potential of targeting CENP-A for cancer therapy.