In the last few years, considerable interest has been generated in the role of high-mobility-group (HMG) proteins, and HMG box proteins generally, in cancer development and therapy. These proteins were discovered in the early 1970s (Goodwin et al. 1973) as a group of nonhistone proteins. Some members of the HMG protein family (i) constitute a class of important architectural proteins involved in transcriptional regulation of genes, (ii) are frequently expressed in transformed cells at levels that correlate with the degree of neoplastic cell transformation, (iii) participate in gene rearrangements, which are linked to the emergence of benign solid tumors, (iv) confer the ability to recognize DNA-cisplatin adducts selectively, and (v) provide a new delivery system for efficient gene transfer. It should be considered that some HMG proteins, acting as architectural proteins that bring many of the transcription factors into precise three-dimensional shapes, may have a similar critical role in neoplastic transformation to that of some transcription factors themselves.