Cytosine methylation in DNA constitutes an important epigenetic layer of transcriptional and regulatory control in many eukaryotes. Profiling DNA methylation across the genome is critical to understanding the influence of epigenetics in normal biology and disease, such as cancer. Genome-wide analyses such as arrays and next-generation sequencing (NGS) technologies have been used to assess large fractions of the methylome at a single-base-pair resolution. However, the range of DNA methylation profiling techniques can make selecting the appropriate protocol a challenge. This chapter discusses the advantages and disadvantages of various methylome detection approaches to assess which is appropriate for the question at hand. Here, we focus on four prominent genome-wide approaches: whole-genome bisulfite sequencing (WGBS); methyl-binding domain capture sequencing (MBDCap-Seq); reduced-representation-bisulfite-sequencing (RRBS); and Infinium Methylation450 BeadChips (450 K, Illumina). We discuss some of the requirements, merits, and challenges that should be considered when choosing a methylome technology to ensure that it will be informative. In addition, we show how genome-wide methylation detection arrays and high-throughput sequencing have provided immense insight into ovarian cancer-specific methylation signatures that may serve as diagnostic biomarkers or predict patient response to epigenetic therapy.