The past two decades have seen great progress in the elucidation of the genetic basis of human genetic disease. Many clinical phenotypes have been linked with mutations or deletions in specific causative genes. However, it is often less recognized that in addition to the integrity of the protein-coding sequences, human health critically also depends on the spatially, temporally, and quantitatively correct expression of those genes. Genetic disease can therefore equally be caused by disruption of the regulatory mechanisms that ensure proper gene expression. The term "position effect" is used in those situations where the expression level of a gene is deleteriously affected by an alteration in its chromosomal environment, while maintaining an intact transcription unit. Here, we review recent advances in our understanding of the possible mechanisms of a number of "position effect" disease cases and discuss the findings with respect to current models for genome organization and long-range control of gene expression.