Despite significant advances in deciphering the molecular events underlying genomic function, our understanding of these integrated processes inside the functioning cell nucleus has, until recently, met with only very limited success. A major conundrum has been the "layers of complexity" characteristic of all cell structure and function. To understand how the cell nucleus functions, we must also understand how the cell nucleus is put together and functions as a whole. The value of this neo-holistic approach is demonstrated by the enormous progress made in recent years in identifying a wide variety of nuclear functions associated with the nuclear matrix. In this article we summarize basic properties of in situ nuclear structure, isolated nuclear matrix systems, nuclear matrix-associated functions, and DNA replication in particular. Emphasis is placed on identifying current problems and directions of research in this field and illustrating the intrinsic heuristic value of this global approach to genomic organization and function.