Stroma is an integral part of solid tumors and plays a key role in growth promotion and immune suppression. Most current therapies focus on destroying tumors and/or abnormal vasculature. However, evidence is emerging that anticancer efficacy improves with vessel normalization rather than destruction. Specific targeting of cytokines into tumors provides proof-of-concept that tumor stroma is dynamic and can be remodeled to increase drug access and alleviate immune suppression. Changing the inflammatory milieu ‘opens’ tumors for therapy and thus provides a license for destruction. This involves reprogramming of paracrine signaling networks between multiple stromal components to break the vicious cycle of angiogenesis and immune suppression. With active immunotherapy rapidly moving into the clinic, local cytokine delivery emerges as an attractive adjuvant.