The ICF syndrome is a rare, autosomal recessive disorder, often fatal in childhood, and characterized by genetic and clinical heterogeneity. Its most consistent features are reduction in serum immunoglobulin levels, facial anomalies, and cytogenetic defects. ICF is also characterized by abnormal DNA methylation. Significant DNA hypomethylation is present mainly in the classical satellite sequences, the major constituent of the juxtacentromeric heterochromatin of chromosomes 1, 9, and 16. The relationship between DNA methylation defects, altered gene expression, and clinical and phenotypic features in ICF has been the object of intense scrutiny. Although the full pathogenetic picture remains to be elucidated, a number of hypotheses advocating an epigenetic model for this syndrome have been advanced by different research groups. Central to some of these hypotheses is the postulation of a trans-acting regulatory role for the heterochromatin and the suggestion of a possible connection between altered gene expression in ICF and the inappropriate release or recruitment of regulatory complexes by the hypomethylated satellite DNA. This chapter reviews the evidence supporting an association between pathology, large-scale chromatin organization, and nuclear architecture in this enigmatic syndrome.