The high mobility group protein 2 (HMGA2) is a protein of less than 12 kDa, that consists of 108 amino acids and which is coded by the HMGA2 gene located at 12q13-15. The first three (of five) exons encode the AT-binding domain site, which can bind to AT-rich binding sites in the DNA minor groove. These bindings affect the conformation of the DNA and modify transcription by enhancing or suppressing the activities of numerous genes. As such, HMGA2 is an essential component of the enhanceosome. Instead of direct regulation, HMGA2 alters the architecture of DNA and supports the assembly of protein complexes that do regulate the transcription of genes. HMGA2 is preferentially expressed during organogenesis and – with few exceptions – it is hardly expressed in adult tissues. HMGA2 appears to be essential for cell growth regulation. A knock-out of the HMGA2 counterpart in mice results in diet-induced obesity. Specific HMGA2 mutations can lead to unusually small size in mice. Genome-wide association studies have found a relationship between height of humans and HMGA2-linked SNPs. Data suggesting a role of HMGA2 in cancer are rapidly accumulating. Aberrant expression of HMGA2 in adult tissues is commonly associated with both benign and malignant tumor formation. HMGA2 is often re-expressed in human tumors, where it promotes tumorigenesis by multiple mechanisms. HMGA2 was found to increase cancer cell proliferation, inhibit apoptosis, impact several DNA repair mechanisms, endorse epithelial-mesenchymal transition, support a cancer stem cell phenotype, and to foster cancer cell resistance to chemotherapeutic agents. Causes for HMGA2 re-expression in neoplastic tissues include gene fusion, amplification, regulation by specific miRNAs, and other mechanisms.