Multiple mechanisms of resistance to antiangiogenic therapies arise depending on the tumor type and microenvironment, and the different stromal components and functions are key for the full resistance phenotype. Cascone et al. (13) tackle the question of resistance to anti-VEGF therapy in NSCLC tumors by using a relatively refractory xenograft model (left) and two acquired resistance models (right). In the partially refractory model, anti-VEGF therapy does not alter tumor growth, but induces disorganized sprouting revascularization that leads to more tortuous vasculature with lower pericyte coverage, concomitant with endothelial upregulation of p-EGFR in treated tumors. In the case of acquired resistance, tumors initially respond to anti-VEGF therapy, but rapidly acquire resistance with efficient revascularization following a pattern of pericyte-covered normalized vasculature with increased activated EGFR on perivascular cells. Differences in the repertoire of proangiogenic growth factors expressed in each of these cases drive the mechanisms of stromal resistance to antiangiogenic therapies.