RNA-binding proteins (RBPs) play essential roles in both transcription and post-transcriptional regulation of RNA, including splicing, cleavage, processing, polyadenylation, RNA modifications, transport, and translation. However, mapping of RBP binding sites has mostly focused on co-transcriptional regulation. Here Zhang et al.1 use data generated during ENCODE phase III to map and characterize regulatory elements that are involved in post-transcriptional regulation. These datasets include high-quality RBP binding profiles generated by enhanced crosslinking and immunoprecipitation (eCLIP) for 112 unique RBPs; Bind-n-Seq experiments that assess the binding specificity of 76 RBPs; and quantitative transcription profiling by RNA-seq in 472 RBP knockdown experiments. These datasets were integrated with genetic variability data to characterize both sequence and structural conservation in RBP binding sites. The authors also characterized the network features of the RBP regulome and identified binding hubs that are associated with higher conservation. All this information was integrated into a variant-scoring framework, named RADAR (RNA Binding Protein Regulome Annotation and Prioritization). Using gene expression data from The Cancer Genome Atlas for 19 different cancers, RADAR identified candidate RBPs that might have important regulatory roles in these — and indeed, many had been previously associated with cancer, thus demonstrating RADAR’s potential to identify disease-relevant variants. Overall, this study presents a comprehensive view of the post-transcriptional mammalian regulome and a framework for prioritizing the study of regulatory variants.