Fludarabine monotherapy is an established treatment for chronic lymphocytic leukemia (CLL), achieving superior remission rates compared with other treatment regimens containing alkylating agents or corticosteroids. However, CLL remains incurable and research continues into finding new treatments for this, the most common leukemia in the Western world. Recent research has focused on the use of fludarabine in combination with other chemotherapeutic agents. Studies published to date indicate that regimens containing fludarabine plus cyclophosphamide, with or without mitoxantrone, achieve overall response (OR) rates of 64-100% and complete response (CR) rates of up to 50%. Administration of cyclophosphamide at a lower dosage (< or =300 mg) appears to reduce the risk of myelosuppression without compromising efficacy. Combinations of fludarabine with prednisone or chlorambucil have been shown to be no more effective than fludarabine monotherapy (OR 27-79% with these combinations), while the combination of fludarabine plus cytarabine proved to be less effective than fludarabine monotherapy. Further studies are needed to evaluate the combinations of fludarabine plus doxorubicin and fludarabine plus epirubicin, as results to date have been inconclusive. More trials are also needed to examine a fludarabine, cytarabine, mitoxantrone and dexamethasone combination that has achieved a promising CR rate of 60% in the one trial reported thus far. Taken together, the results obtained so far with fludarabine plus cyclophosphamide suggest that this combination is more potent than fludarabine monotherapy and is able to increase the CR rate, the OR rate, event-free survival and progression-free survival in patients with CLL.