DNA methylation is the most studied epigenetic modification in vertebrates. It is a conserved process that involves the addition of a methyl group on cytosine residues in CpG dinucleotides and has been implicated in gene expression and regulation. Due to this integral relationship with gene expression, DNA methylation has been associated with the normal cell development and functions, including imprinting and X-inactivation (1,2) as well as the development and progression of several diseases ranging from autoimmune diseases to cancer and neurological diseases. Furthermore, distinct tissue-specific methylation patterns have been investigated for their role as biomarkers for disease screening, prognosis, and progression. This chapter focuses on DNA methylation and its implications in the clinical setting.