Abstract: Disclosed herein is an assay for identifying compounds that modulate the interaction between p53 and specific DNA binding sites. The assay uses chromatin-assembled target genes to correctly reproduce p53 binding to target genes of interest. This assay permits the selection of compounds which preferentially associate with p53 when bound to specific DNA binding sites but not others. Moreover, compounds can be screened for their ability to selectively modulate p53 interaction with specific binding sites associated with individual genes. Compounds can also be screened for their ability to selectively modulate p53 interaction with specific cofactors (proteins, nucleic acids, peptides, etc.) when p53 is bound to specific DNA sequences. This system allows drugs to be tailored to affect p53-dependent regulation of certain target genes that regulate distinct cellular pathways without affecting other genes and pathways.