The development of novel treatment strategies for therapy of angiogenesis-dependent diseases requires identification of specific tumor endothelial cell markers to which therapeutic agents can be targeted. This can be achieved by random or targeted approaches. Random approaches are based on genomic screening to identify differences between normal and activated endothelium. Targeted approaches utilize known angiogenesis inhibitors to find their molecular targets. Both approaches may lead to the development of angiostatic therapies that are directly targeted towards activated endothelial cells. This review summarizes the recent developments in both approaches.