Running title: A map of cis-regulatory modules in the human genome ABSTRACT Annotating all cis-regulatory modules (CRMs) in genomes is essential to understand genome functions, however, it remains an uncompleted task despite great progresses made since the development of ChIPseq techniques. As a continued effort, we developed a new algorithm dePCRM2 for predicting CRMs and constituent transcription factor (TF) binding sites (TFBSs) by integrating numerous TF ChIP-seq datasets based on a new ultra-fast, accurate motif-finding algorithm and an efficient combinatory motif pattern discovery method. dePCRM2 partitions genome regions covered by extended binding peaks in the datasets into a CRM candidates (CRMCs) set and a non-CRMCs set, and predicts CRMs and constituent TFBSs by evaluating each CRMC using a novel score. Applying dePCRM2 to 6,092 datasets covering 77.47% of the human genome, we predicted 201 unique TF binding motif families and 1,404,973 CRMCs.Intriguingly, the CRMCs are under stronger evolutionary constraints than the non-CRMCs, and the higher a CRMC can score, the stronger evolutionary constraint it receives and the more likely it is a full-length enhancer. When evaluated on functionally validated VISTA enhancers and causal ClinVar mutants, dePCRM2 achieves 97.43~100.00% sensitivity at p-value ≤ 0.05. dePCRM2 also largely outperforms existing methods in sensitivity and specificity, as well as by the evaluation of evolution constraints.Based on our predictions and evolutionary behaviors of the genome, we estimated that about 21.95% and 54.87% of the genome might code for TFBSs and CRMs, respectively, for which we predicted 80.21%. CRMs, rather than coding sequences (CDSs), that mainly account for inter-species divergence and intraspecies diversity (