Cul4-Ddb1, a RING H2 ubiquitin ligase, plays an important role in many vital cellular processes including DNA replication, DNA repair and transcription. Recent research reveals strong links between Cul4-mediated signaling pathways and chromatin biology. Ubiquitylation of substrates by Cul4-Ddb1 occurs on chromatin and is initiated by chromatin-based signals that either recruit Cul4-Ddb1 to chromatin or alter the activity of the ligase. This includes Cul4-mediated ubiquitylation of the replication licensing factor, Cdt1; a process that requires chromatin-bound PCNA and Cdt2, a member of the recently identified family of candidate substrate receptors for Cul4 (termed Ddb1- and Cul4-associated factors: DCAFs). The activity of two other Cul4-based ubiquitin ligases, Cul4-Ddb1(Ddb2) and Cul4-Ddb1(CSA), are differentially regulated by the COP9 signalosome in response to different chromatin-based signals. Finally, examples of direct modifications to chromatin by Cul4-Ddb1 have emerged, including ubiquitylation of histones and the recruitment of enzymes involved in chromatin remodeling or histone methylation.