Mistletoe lectin I (ML-I) is a heterodimeric ribosome-inactivating protein composed of a sialic acid-specific Bchain that binds to cell surfaces, and an A-chain with the capacity to depurinate a critical adenosine in the 28S ribosomal RNA. ML-1, in purified or recombinant form, exerts an immunomodulatory effect on neutrophils and macrophages/ monocytes in the low-dose range, while at high doses, it induces apoptosis in both normal and tumoral cells. While mistletoe extracts are widely used as cancer adjuvant therapy, recombinant ML-I (rAviscumin) is a candidate antineoplastic agent that has successfully passed Phase I clinical trials. In immunodeficient mouse models, the efficacy of recombinant ML-I was demonstrated for ovarian carcinoma, melanoma and various hematological malignant cell lines. The clinical potential of recombinant ML-I as a non-mutagenic and non-genotoxic molecule is high and could be used to potentiate classical anti-neoplastic drugs. Its capacity to induce apoptosis in cancer cell lines lacking p53 allows considering its use against genetically unstable and highly metastatic cancers. The mechanisms of apoptosis induced by ML-I probably involves intracellular pathways akin to those described as the “ribotoxic stress response” that directly target the mitochondrion.