Discovery of transcription regulatory elements has been an enormous challenge, both to biologists and computational scientists. Over the last three decades, significant progress has been achieved by various laboratories around the world. Earlier, laborious experimental methods were used to detect one or handful of elements at a time. With recent advances in DNA sequencing technology, many completed genomes became available. High throughput biological techniques and computational methods emerged. Comparative genomic approaches and their integration with microarray gene expression data provided promising results. In this review, we discuss the development of technology to decipher the complex transcription regulation system with a focus on the discovery of cis-regulatory elements in eukaryotes.