Immunotherapeutic approaches to leptomeningeal metastasis (LM) include the intrathecal application of cytokines such as interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), and lymphokine-activated killer cells (LAK cells). Results in a rodent model of leptomeningeal gliomatosis with intrathecal IL-2 application are discouraging, but some clinical improvement and clearance of neoplastic cells from CSF have been seen in patients with LM from melanoma treated with intrathecal IL-2 alone, and in patients with LM from primary brain tumors and squamous cell carcinoma of the tongue treated with intrathecal LAK cells and IL-2. The neurotoxicity of this therapy, mainly increased intracranial pressure, has been considerable but generally manageable. However, IFN-alpha caused severe neurotoxicity in form of an only partly reversible progressive vegetative state in the majority of patients. Considering the small number of patients treated with IL-2 and LAK cells, its value for the treatment of LM could only be stated by further investigation. In future, the application of recently discovered cytokines such as Fas-ligand, the continuous paracrine cytokine release by genetically modified cells, or vaccination strategies using genetically modified tumor cells might offer new immunotherapeutic approaches in LM.