Members of the HMGA (a.k.a. HMGI/Y) family of 'high mobility group' (HMG) proteins participate in a wide variety of nuclear processes ranging from chromosome and chromatin mechanics to acting as architectural transcription factors that regulate the expression of numerous genes in vivo. As a consequence, they function in the cell as highly connected 'nodes' of protein-DNA and protein-protein interactions that influence a diverse array of normal biological processes including growth, proliferation, differentiation and death. The HMGA proteins, likewise, participate in pathological processes by, for example, acting as regulators of viral gene transcription and by serving as host-supplied proteins that facilitate retroviral integration. HMGA genes are bona fide proto-oncogenes that promote tumor progression and metastasis when overexpressed in cells. High constitutive HMGA protein levels are among the most consistent feature observed in all types of cancers with increasing concentrations being correlated with increasing malignancy. The intrinsic attributes that endow the HMGA proteins with these remarkable abilities are a combination of structural, biochemical and biological characteristics that are unique to these proteins. HMGA proteins have little, if any, secondary structure while free in solution but undergo disordered-to-ordered structural transitions when bound to substrates such as DNA or other proteins. Each protein contains three copies of a conserved DNA-binding peptide motif called the 'AT-hook' that preferentially binds to the minor groove of stretches of AT-rich sequence. In vivo HMGA proteins specifically interact with a large number of other proteins, most of which are transcription factors. They are also subject to many types of in vivo biochemical modifications that markedly influence their ability to interact with DNA substrates, other proteins and chromatin. And, most importantly, both the transcription of HMGA genes and the biochemical modifications of HMGA proteins are direct downstream targets of numerous signal transduction pathways making them exquisitely responsive to various environmental influences. This review covers recent advances that have contributed to our understanding of how this constellation of structural and biological features allows the HMGA proteins to serve as central 'hubs' of nuclear function.