Chimeric antigen receptor (CAR) T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in chronic lymphocytic leukemia (CLL) patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumors. In this review, we discuss the antigenic targets exploited in CLL CAR-T therapy, the determinants of favorable responses, as well as the mechanisms of treatment failure specific to this disease.