Fludarabine (Flu), a purine nucleoside analogue, is the firstline drug for patients with chronic lymphocytic leukemia (CLL), and can induce apoptosis of malignant cells in CLL patients. However, CLL remains an incurable disease. Fludarabine-resistance is one of the predominant reasons for treatment failure. In this paper, the metabolism, action and drug-resistance mechanisms of Fludarabine in CLL as well as possible reversible strategies are reviewed, with particular emphasis on recent advances in the characterization of nucleoside transporters and p53-mediated apoptosis and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to Flu.