The integrins play key roles in the signaling networks that drive pathological angiogenesis and tumor progression. Integrin β4 is a laminin receptor upregulated in tumor cells and angiogenic endothelial cells. Biochemical studies have indicated that β4 combines with and enhances the signaling function of multiple receptor tyrosine kinases, including ErbB2, EGF-R and Met. Genetic studies have revealed that β4 signaling promotes both angiogenesis and tumorigenesis. Here, I discuss the hypothesis that β4 promotes both processes by amplifying receptor-tyrosine-kinase signaling. Therefore, I propose that a simultaneous blockade of β4 and receptor-tyrosine-kinase signaling represents a rational approach to cancer and anti-angiogenic therapy.