The integrins play key roles in the signaling networks that drive pathological angiogenesis and tumor progression. Integrin beta4 is a laminin receptor upregulated in tumor cells and angiogenic endothelial cells. Biochemical studies have indicated that beta4 combines with and enhances the signaling function of multiple receptor tyrosine kinases, including ErbB2, EGF-R and Met. Genetic studies have revealed that beta4 signaling promotes both angiogenesis and tumorigenesis. Here, I discuss the hypothesis that beta4 promotes both processes by amplifying receptor-tyrosine-kinase signaling. Therefore, I propose that a simultaneous blockade of beta4 and receptor-tyrosine-kinase signaling represents a rational approach to cancer and anti-angiogenic therapy.