Targeted therapy against cancer shows not only promise, but also limits. No matter how specific the target, many pathways and cell types can be affected, some unexpectedly. A tumor is heterogeneous and plastic; it can evade a targeting agent or an attack mechanism. Local regulatory factors contribute to site-specific effects. In the brain, widely disseminated tumor, including microscopic tumor, local regulatory differences and impediments to brain-wide delivery can all limit the efficacy of any single agent or approach. Provocatively, precedents for both problems and solutions are seen in the original targeted therapy, the immune response.