There are approx 8000 new cases of chronic lymphocytic leukemia (CLL) a year in the United States (1). Most patients eventually progress to an advanced stage or develop rapidly progressive disease with a median survival of only 18–36 mo (2). Although allogeneic bone marrow transplantation (including nonmyeloablative conditioning regimens) offers the possibility of longterm remission or cure (3), most patients either lack suitable donors and have comorbidities that prevent such therapy. Monoclonal antibodies, radiolabeled antibody conjugates, and antibody-drug conjugates have been used in CLL and have produced clinical remissions, but most of the responses have been partial and have not been durable. Hence, additional novel agents that may significantly impact on the natural history of this disease are needed. One such class of agents is the immunotoxins consisting of monoclonal antibodies, antibody fragments, or cytokines linked either chemically or genetically to peptide toxins. The antibody or cytokine directs the molecule to the CLL cell surface. The toxin moiety is internalized and translocated to the cytosol, where it enzymatically inactivates protein synthesis inducing programmed cell death. In this review, we discuss the unique biology of the CLL cell that makes it an attractive candidate for immunotoxin therapy. We describe potential CLL cell surface receptors for targeting with immunotoxins as well as the structure and function of selected CLL immunotoxins. Finally, the clinical results of previous and on-going clinical trials with these agents in CLL are analyzed.