Long-standing studies have clearly established that the architectural chromatinic proteins High Mobility Group A (HMGA) are among the most widely expressed cancer-associated proteins. Indeed, their overexpression represents a constant feature of human malignancies, and correlates with a poor prognosis. Moreover, HMGA dysregulation, as a result of specific chromosomal rearrangements, occurs in a broad variety of common benign mesenchymal tumors, making HMGA genes among the most commonly rearranged genes in human neoplasms. Nevertheless, recent data propose a critical role of HMGA overexpression also in the generation of pituitary adenomas. Here, we review the involvement of HMGA proteins in cancer, analyzing the mechanisms underlying their crucial role in tumorigenesis, and, finally, discuss the potentiality of a cancer treatment based on HMGA targeting.