The vasculature of solid tumors is fundamentally different from that of normal vasculature and offers a unique target for anti-cancer therapy. Direct vascular-targeting with Tumor-Vascular Disrupting Agents (Tumor-VDAs) is distinctly different from anti-angiogenic strategies, and offers a complementary approach to standard therapies. Tumor-VDAs therefore have significant potential when combined with chemotherapy, radiotherapy, and angiogenesis-inhibiting agents. Preclinical studies with the different Tumor-VDA classes have demonstrated key tumor-selective anti-vascular and anti-tumor effects.