Immunotoxins (monoclonal antibodies chemically coupled to peptide toxins) and fusion toxins (peptide ligands fused genetically to peptide toxins) have been used to treat a variety of malignancies over the last 20 years. Problems with normal tissue toxicities (vascular leak syndrome, hepatotoxicity, and neurotoxicities), poor penetration to tumor interstitum, and humoral immune responses have limited clinical efficacy. Higher response rates were observed with systemic therapy of leukemias and lymphomas and regional therapy of primary brain tumors. Ongoing studies are examining the role of targeted toxins in combination with chemoradiotherapy and in minimal residual disease settings.