When needles look like hay: How to find tissue-specific enhancers in model organism genomes

► For in vivo tests of cis-regulatory region, various experimental shortcuts have been found. ► Cross-species conservation reduces the search space. ► Long-range effects and promoter interactions can complicate the identification. ► Cell culture essays might be of limited use for developmental enhancers. ► Sequence predictions enrich but are not generic enough for most developing tissues.