DNA methylation is an important epigenetic mark with broad relevance in development and disease. Reduced representation bisulfite sequencing (RRBS) enables genome-scale DNA methylation analysis with all the advantages of sequencing technology (accuracy, robustness, flexibility) at a fraction of the cost of whole genome bisulfite sequencing. Diagenode Premium RRBS kit makes this powerful technology readily available to any interested laboratory. Its optimized protocol provides genomic coverage for 3.5 to 4 million CpG dinucleotides in the human genome, which is 5-10 fold higher than the coverage of commercially available DNA methylation microarrays. The method covers not only CpG islands and promoter regions, but also a broad sampling of other functional elements including enhancers, CpG island shores and non-coding RNAs. Finally, its optimized workflow with multiplexing prior to bisulfite conversion allows for convenient processing of up to 96 samples in a single experiment, thus enabling epigenome-wide association studies in large cohorts and in any vertebrate species using an optimized and easy-to-use kit.