CLL remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Honokiol is a natural product known to possess potent anti-neoplastic and anti-angiogenic properties. We examined whether Honokiol can overcome apoptotic resistance in CLL cells. Honokiol induces caspase-dependent cell death of CLL cells, characterized by an increase in Annexin V positive, propidium iodide negative cells that was blocked by the caspase inhibitor, Z-VAD-fmk. Further evidence for Honokiol-induced apoptosis of CLL cells was confirmed by an increase in caspase 3 activity and cleavage of PARP. In addition, Honokiol demonstrated an LC50 that was lower for CLL cells than for normal mononuclear cells, suggesting that CLL cells are more susceptible to the cytotoxic effects of Honokiol compared to normal hematopoietic cells. To determine whether Honokiol-induced apoptosis of CLL cells was associated with known positive therapeutic effects, we examined mcl-1 expression, a survival protein whose down-regulation is associated with response to treatment in CLL patients. Honokiol treatment of CLL cells resulted in a significant decrease in the expression of mcl-1 within 24 hours. Furthermore, CLL cells pre-treated with IL-4, a cytokine known to support CLL survival, underwent apoptosis when subsequently incubated with Honokiol, indicating that Honokiol could also overcome the pro-survival effects of IL-4. These data indicate that Honokiol is a potent inducer of apoptosis in CLL cells and should be examined for further clinical application.