Abstract: Deciphering the noncoding regulatory genome has proved a formidable challenge. Despite the wealth of available gene expression data, there currently exists no broadly applicable method for characterizing the regulatory elements that shape the rich underlying dynamics. We present a general framework for detecting such regulatory DNA and RNA motifs that relies on directly assessing the mutual information between sequence and gene expression measurements. Our approach makes minimal assumptions about the background sequence model and the mechanisms by which elements affect gene expression. This provides a versatile motif discovery framework, across all data types and genomes, with exceptional sensitivity and near-zero false-positive rates. Applications from yeast to human uncover putative and established transcription-factor binding and miRNA target sites, revealing rich diversity in their spatial configurations, pervasive co-occurrences of DNA and RNA motifs, context-dependent selection for motif avoidance, and the strong impact of posttranscriptional processes on eukaryotic transcriptomes.