During human neutrophil differentiation, large portions of the genome condense and associate with the nuclear envelope to form filament-like structures. As a result, the nucleus of the mature neutrophil typically consists of a linear array of three or four lobes joined by thin, DNA-containing filaments. Despite the medical significance of neutrophil nuclear morphology, little is known about the events regulating neutrophil nuclear differentiation and its pathological states. This work presents a new model of the mechanisms governing nuclear filament formation in human neutrophils. This model is based on recent chromosome mapping studies in human neutrophils and on studies of genetic and pathological conditions affecting neutrophil nuclear shape. According to this model, filament assembly is initiated by factors that interact with specific regions of the genome in a hierarchical and dose-dependent manner. In this regard, the strategies governing the molecular interactions responsible for filament formation appear to resemble those involved in transcriptional silencing, a phenomenon that also affects the properties of extended chromosomal regions. According to the silencing paradigm, bound filament control Factors must recruit additional Filament Foehn factors which spread along adjacent DNA to mediate filament formation. A better understanding of the factors that shape the neutrophil nucleus may lead to new clinical tools for the diagnosis and manipulation of abnormal neutrophil differentiation.