In this issue of Blood, Ang et al(1) show that human CD20 messenger RNA (mRNA) undergoes alternative splicing to generate distinct 5' untranslated region (5'-UTR) variants, which determine the cell-surface CD20 levels in malignant B cells and the interpatient variability in the expression of this therapeutic target. These variants can also be used as an escape mechanism from anti-CD20 therapies.