Histological assessment of nuclear morphology is a standard procedure in clinical practice. The implications of altered nuclear structure accompanying neoplastic disease are still not fully understood. Nuclear matrix proteins were considered as structural units defining the shape of nuclei. Consequently, it was assumed that nuclei displaying characteristics of cancer cells would exhibit specific nuclear matrix proteins. The nuclear proteome was investigated by various approaches, including analyses of preparations of whole nuclei, the nuclear matrix and of subnuclear compartments. Proteome alterations related to cancer were mainly investigated by comparative two dimensional polyacrylamide gel analyses. This review provides an overview of results achieved by this and other proteome analysis approaches, highlighting some implications of technical and analytical details. The contribution and future potential of proteomics to the further understanding of the chromatin regulation and mechanisms affecting nuclei during cell transformation will be discussed with regard to important advances accomplished by current techniques.