Mantle Cell Lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells in the mantle zone of lymph nodes. Parekh and his collaborators analyzed genome-wide methylation in MCL patients using the HELP (HpaII tiny fragment Enrichment by Ligation mediated PCR) assay and found significant aberrancy in promoter methylation patterns as compared to normal naïve B cells. Using biological and statistical criteria, he identified four hypermethylated genes CDKN2B, MLF-1, PCDH8, HOXD8 and four hypomethylated genes CD37, HDAC1, NOTCH1 and CDK5 where aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the HDAC inhibitor SAHA in induction of the hypermethylated genes and anti-MCL cytotoxicity. Parekh’s finding indicate prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in this disease.