Lymphoid malignancies, mainly including lymphocytic leukemia and lymphoma, are a group of heterogeneous diseases. Although the clinical outcome of patients has been significantly improved with current immuno-chemotherapy, definitive biomarkers remain to be investigated, particularly those reflecting the malignant behavior of tumor cells and those helpful for developing optimal targeted therapy. Recently, genome-wide analysis reveals that altered genetic methylations play an important role in tumor progression through regulation of multiple cellular transduction pathways. This review describes the pathogenetic effect of the aberrant genetic methylation in lymphoid malignancies, with special emphasis on potential therapeutic strategies targeting key signaling networks.