Finding the genetic causes for complex diseases is a challenge. Expression studies have shown that the level of expression of many genes is altered in disease compared with normal conditions, but what lies behind these changes? Linkage studies provide hints as to where in the genome the genetic triggers – the mutations – might be located. Fine-mapping and association studies can give yet more information about which genes, and which changes in the genes, are involved in the disease. Recent examples show that single-nucleotide polymorphisms (SNPs), which are variations at the single-nucleotide level within an individual's DNA, in the regulatory regions of some genes constitute susceptibility factors in many complex diseases. This article discusses the nature of regulatory SNPs (rSNPs) and techniques for their functional validation, and looks towards what rSNPs can tell us about complex diseases.