The nucleus of the human pathogen Trypanosoma brucei not only has unusual chromosomal composition, characterised by the presence of megabase, intermediate and minichromosomes, but also chromosome and gene organisation that is unique amongst eukaryotes. Here I provide an overview of current knowledge of nuclear structure, chromatin organisation and chromosome dynamics during interphase and mitosis. New technologies such as chromatin immunoprecipitation, in combination with new generation sequencing and proteomic analysis of subnuclear fractions, have led to novel insights into the organisation of the nucleus and chromatin. In particular, we are beginning to understand how universal mechanisms of chromatin modifications and nuclear position effects are deployed for parasite-specific functions and are centrally involved in genomic organisation and transcriptional regulation. These advances also have a major impact on progress in understanding the molecular basis of antigenic variation.