The genomic information embedded in the primary nucleotide sequence of DNA is modulated by epigenomic code generated from chemical modifications of DNA bases and key DNA-interacting proteins such as the histones. The methylation of cytosines leading to the formation of 5-methylcytosines (5mCs), for example, provides a major means for the modification of the primary DNA code. As detailed in Chapter 2, DNA methylation plays important roles in many biological functions such as embryonic development, cell differentiation, and stem cell pluripotency, by regulating gene expression and chromatin remodeling. Abnormal patterns of DNA methylation, on the other hand, lead to diseases such as cancer. DNA methylome analysis, as a key component of epigenomics, has for many years been conducted with the use of microarrays (such as the Illumina Infinium 450K BeadChips). Although microarrays are low-cost and easy to use, their inherent constraints, such as limited genomic coverage from the use of preselected probes and being available for only a few model organisms, have limited their use. In comparison, next-generation sequencing (NGS) offers a more unbiased, comprehensive, and quantitative approach for the study of DNA methylation status in a wide array of species. This chapter is focused on DNA methylation sequencing data generation and analysis. For epigenomic studies that involve interrogation of histone modifications, ChIP-Seq (covered in Chapter 11) can be used.