A definitive diagnosis of cancer may be rendered by microscopic assessment of only a few cells in an appropriate clinical setting due to the distinctive nuclear structure of most cancer cells in comparison to nuclei of normal human cells. The molecular architecture of non-neoplastic human nuclei—of the nuclear matrix and of matrix-associated proteins and nucleic acids—is being characterized in exquisite molecular detail. What is missing is the application of the findings and tools of molecular biology to understanding the cytological structure of cancer nuclei. This article delves into the basis of nuclear structure at different levels of resolution—light microscopic, electron microscopic, and molecular. J. Cell. Biochem. 104: 1994–2003, 2008. © 2007 Wiley-Liss, Inc.