In the past few years accumulating evidence involved chromosomal instability and the subsequent aneuploidy that it generates in tumor formation. Moreover, the misregulation of most of the proteins involved in the mitotic checkpoint as well as kinetochore assembly has proven to have tumorigenic potential in vivo. Thus, the overexpression of Ndc80/Hec1, an outer kinetochore protein involved in spindle assembly checkpoint (SAC) recruitment, has been shown to induce tumor formation in different organs. Since Ndc80/Hec1 is a protein “ highly expressed in cancer” , it is an attractive target that can be used for cancer therapy. In this direction, several strategies aiming to in vivo block this complex structure and activity are being developed, and some of them have demonstrated to have tumor growth inhibition potential. These therapies represent a potential interesting approach for the treatment of malignancies where Ndc80/Hec1 expression is upregulated. Here we will discuss different aspects of Ndc80/Hec1 biology, its role in kinetochore assembly and spindle checkpoint, and its importance as a potential therapeutical target.