We observed that IL‐21 and IL‐4 exert opposing effects on CD40‐mediated Bcl‐XL expression, where IL‐21/STAT3 signalling reduced and IL‐4/STAT6 signalling augmented Bcl‐XL expression via direct transcriptional regulation as well as by interfering with NF‐κB signalling activity, thereby influencing CLL drug resistance. The gene discussed is NFKB1; the disease is B-cell chronic lymphocytic leukemia.