Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins' overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.