The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions, now called nucleolar organizer regions or NORs, are known to contain the genes encoding ribosomal RNA (rRNA).

The structure and number of nucleoli vary depending on the requirement for ribosomal RNA synthesis. Thus, the specific state of differentiation of a cell can be identified from its nucleoli. In aggressive breast cancer cells, the nucleolus becomes 30% larger during tumor progression, which demands heightened ribosomal production. Transversely, in lymphocytes, ribosome synthesis is terminated at the final stage of cell differentiation. Consequently, the nucleoli reduce in size to become tiny fibrillar structures.

The nucleolus consists of three distinct structural regions: the fibrillar center, dense fibrillar component, and granular component. The different regions correspond to the sites of rRNA transcription, processing, and ribosomal assembly, at different stages. The fibrillar centers contain rRNA genes that are transcribed at the boundary separating them from the dense fibrillar component. Processing of precursor rRNAs starts in the dense fibrillar component and extends in the granular component, where the processed rRNAs are assembled with ribosomal proteins. The newly formed pre-ribosomal subunits are then exported to the cytoplasm for further processing into mature ribosomes.