The spatiotemporally and quantitatively correct activity of a gene requires the presence of intact coding sequence as well as properly functioning regulatory control. One of the great challenges of the post-genome era is to gain a better understanding of the mechanisms of gene control. Proper gene regulation depends not only on the required transcription factors and associated complexes being present (in the correct dosage), but also on the integrity, chromatin conformation and nuclear positioning of the gene's chromosomal segment. Thus, when either the cis-trans regulatory system of a gene or the normal context of its chromatin structure are disrupted, gene expression may be adversely affected, potentially leading to disease. As transcriptional regulation is a highly complex process depending on many factors, there are many different mechanisms that can cause aberrant gene expression. Traditionally, the term 'position effect' was used to refer to situations where the level of expression of a gene is deleteriously affected by an alteration in its chromosomal environment, while maintaining an intact transcription unit. Over the past years, an ever increasing number of such disease-related position effect cases have come to light, and detailed studies have revealed insight into the variety of causes, which can be categorized into a number of different mechanistic groups. We suggest replacing the outdated term of 'position effect disease' with the new generic name of 'cis-ruption disorder' to describe genetic disease cases that are caused by disruption of the normal cis-regulatory architecture of the disease gene locus. Here, we review these various cis-ruption mechanisms and discuss how their studies have contributed to our understanding of long- range gene regulation.