The high-mobility group A (HMGA) proteins are frequently overexpressed in human malignancies and correlate with the presence of metastases and reduced patient survival. Here, we highlight the main studies evidencing a critical role of HMGA in chemoresistance, mainly by activating Akt signaling, impairing p53 activity, and regulating the expression of microRNAs that target genes involved in the susceptibility of cancer cells to antineoplastic agents. Therefore, these studies account for the association of HMGA overexpression with patient poor outcome, indicating the impairment of HMGA as a fascinating perspective for effectively improving cancer therapy.