The human genome is predominantly composed of nonprotein-coding sequences whose function remains largely undefined. A significant portion of the noncoding DNA is believed to serve as transcriptional regulatory elements that control gene expression in specific cell types at appropriate developmental stages. Identifying these regulatory sequences and determining the mechanisms by which they act present a great challenge in the postgenomic era. Previous investigations using genetic, molecular, and biochemical approaches have uncovered a large number of proteins involved in regulating transcription. Knowledge of the genomic locations of DNA binding for these proteins in the nucleus should define the identity and nature of the transcriptional regulatory sequences and reveal the gene regulatory networks in cells. Chromatin immunoprecipitation (ChIP) is a common method for detecting interactions between a protein and a DNA sequence in vivo. In recent years, this method has been combined with DNA microarrays and other high-throughput technologies to enable genome-wide identification of DNA-binding sites for various nuclear proteins. Here, we review recent advances in ChIP-based methods for genome-wide detection of protein-DNA interactions, and discuss their significance in enhancing our knowledge of the gene regulatory networks and epigenetic mechanisms in cells.