Here we describe chromatin immunoprecipitation (ChIP), a molecular approach that uses formaldehyde cross-linking to investigate genome structure and function. This approach allows us to determine the distribution of histone modifications (e.g., acetylation, methylation), the deposition of histone variants (H2AZ, H3.3, etc.), and the location of sequence-specific and general transcription factors. We introduce well-established ChIP-based methods that allow analysis of protein-DNA interactions in living cells.