CLL patients harboring TP53 defects remain the most challenging group in terms of designing rational and effective therapy. Irrespective of the treatment employed-chemotherapy, chemoimmunotherapy, or pure biological drugs-median survival of these patients does not exceed 3-4 years. This adverse outcome is caused by a less effective response to therapeutics acting through DNA damage induction and relying on the subsequent initiation of apoptosis as well as by virtually inevitable aggressive relapse. Patient proportions with TP53 defects at diagnosis or before first therapy were reported within the range 5-15 %, but they increase dramatically in pretreated cohorts (reported up to 44 %), and also in patients with Richter transformation (50 % harbor TP53 defects). Currently, most laboratories monitor TP53 defect as presence of 17p deletion using I-FISH, but 23-45 % of TP53-affected patients were shown to harbor only mutation(s). In other patients with intact TP53, the p53 pathway may be impaired by mutations in ATM gene coding for the p53-regulatory kinase; however, prognosis of ATM-defective patients is not as poor as those with TP53 abnormalities. Though many novel agents are under development, the monoclonal antibody alemtuzumab and allogeneic stem cell transplantation remain the basic treatment options for TP53-affected CLL patients.