The topologic distribution of interphase chromosomes established by using various cytologic methods and data concerning the DNA-nuclear skeleton interactions in isolated nuclear fractions were reviewed and discussed. Comparison of these different data clearly showed that the position of chromosomes observed in situ is in agreement with the results obtained from isolated nuclear fractions, indicating that all DNA molecules are bound to the peripheral nuclear skeleton. Moreover, the in situ position of the rDNA near the nuclear envelope can be correlated with the existence of a nucleolar skeleton connected to the peripheral nuclear skeleton. Taking into account the discrepant results regarding the actual existence of an internal nuclear skeleton, we attempted to analyze how the various nuclear skeletal structures described in the literature can be involved in both the distribution of chromosomes and in their chromatin organization. As many questions are still unanswered, we considered the modes of investigation that seem to be the most promising.