Although biological therapy has shown promising clinical responses in many cancers including metastatic melanoma, only a subset of patients has shown marked regression of lesions. In most patients, systemic administration of biological therapies with cytokines is associated with severe toxicities. Schwager et al., in this issue of Journal of Investigative Dermatology, have examined the role of immunocytokines L19-IL2 and L19-TNF to minimize toxicities, and in combination with Ipilimumab they report complete regression of tumors using syngeneic mouse models. The results, if confirmed in clinical trials, will have major implications for the treatment of human cancers, including melanomas.