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All cells in the human body contain the same DNA, but they can have very different functions: compare for example a cell in the intestine with a neuron. Cells accomplish this by each expressing a different set of genes, which are located on the DNA, to make cell components. Gene expression is regulated by other parts of the DNA, called ‘enhancers’. Enhancers recruit proteins to turn genes on or off. Interestingly, enhancers can be found close to the gene they regulate, but they can also be located very far away. In this thesis, we studied how enhancers are able to communicate with their genes across long distances. We changed the distance on the DNA between enhancers and genes, or perturbed proteins important for enhancers. Every time, we then measured what happened to the expression of genes. We found that enhancers that are located far away, need to put in more effort to activate their genes. This means that for these enhancers, the conditions in the cell need to be perfect in order for them to function properly. We think this might have been used by evolution: by putting enhancers at a certain distance from their target genes, these genes are not accidentally activated in the wrong cell type. This then only happens in cells with the perfect conditions, where they are indeed really necessary. Our results help us understand gene regulation in general, but also have implications for diseases and treatments that involve enhancer biology, including cancer and specific developmental disorders.