Since the initial reports implicating caveolin-1 (CAV1) in neoplasia, the scientific community has made tremendous strides towards understanding how CAV1-dependent signaling and caveolae assembly modulate solid tumor growth. Once a solid neoplastic tumor reaches a certain size, it will increasingly rely on its stroma to meet the metabolic demands of the rapidly proliferating cancer cells, a limitation typically but not exclusively addressed via the formation of new blood vessels. Landmark studies using xenograft tumor models have highlighted the importance of stromal CAV1 during neoplastic blood vessel growth from preexisting vasculature, a process called angiogenesis, and helped identify endothelium-specific signaling events regulated by CAV1, such as vascular endothelial growth factor (VEGF) receptors as well as the endothelial nitric oxide (NO) synthase (eNOS) systems. This chapter provides a glimpse into the signaling events modulated by CAV1 and its scaffolding domain (CSD) during endothelial-specific aspects of neoplastic growth, such as vascular permeability, angiogenesis, and mechanotransduction.