Changing the landscape may lead to disease. On pages 533–543 of this issue, Malte Spielmann and Stefan Mundlos discuss how structural variations in regulatory parts of the genome can interfere with normal gene regulation and – by doing so – cause disease. The upper part of the cover shows a wild type situation in which a chromosomal looping mechanism involving the binding of transcription factors (TF) brings the enhancer (red) close to the promoter of its target gene leading to tissue-specifi c expression. In the lower part, the enhancer is duplicated, resulting in disturbed gene expression. Other structural variations that can change the regulatory landscape include the deletion∕mutation of enhancer elements or their inversion, and the deletion of insulators (green bar in the cover image). Cover by Malte Spielmann and Stefan Mundlos.