Traditionally eukaryotic genes are considered independently expressed under the control of their promoters and cis-regulatory domains. However, recent studies in worms, flies, mice and humans have shown that genes co-habiting a chromatin domain or “genomic neighborhood” are frequently co-expressed. Often these co-expressed genes neither constitute part of an operon nor function within the same biological pathway. The mechanisms underlying the partitioning of the genome into transcriptional genomic neighborhoods are poorly defined. However, cross-species analyses find that the linkage among the co-expressed genes of these clusters is significantly conserved and that the expression patterns of genes within clusters have co-evolved with the clusters. Such selection could be mediated by chromatin interactions with the nuclear matrix and long-range remodeling of chromatin structure. In the context of human disease, we propose that dysregulation of gene expression across genomic neighborhoods will cause highly pleiotropic diseases. Candidate genomic neighborhood diseases include the nuclear laminopathies, chromosomal translocations and genomic instability disorders, imprinting disorders of errant insulator function, syndromes from impaired cohesin complex assembly, as well as diseases of global covalent histone modifications and DNA methylation. The alteration of transcriptional genomic neighborhoods provides a model for studying epigenetic alterations as quantitative traits in complex common human diseases.