The last decade resulted in many scientific discoveries illuminating epigenetic mechanisms of gene regulation and genome organization. DNA methylation emerged as playing a pivotal role in development and cancer. Genome-wide changes in DNA methylation, including hypermethylation of tumor suppressor genes and genome-wide loss of methylation, are two dominant mechanisms that deregulate gene expression and contribute to chromosomal instability. In this chapter we give an overview of how methylation patterns are established during B-cell development and what machinery is necessary to maintain those patterns. We summarize the current state of knowledge of aberrant changes taking place during and contributing to lymphoid transformation in general and to the development of CLL in particular. We discuss key deregulated biomarkers extensively studied using single-gene approaches and give an overview of a wealth of data that became available from genome-wide approaches, focusing on pathways that are critical for lymphomagenesis. We also highlight epigenetic differences between known prognostic groups of CLL.