Endothelial cells (ECs) form a dynamic monolayer lining the lumen of vessels. While single-cell data have revealed high degrees of heterogeneity amongst ECs at the inter- and intra-organ levels, the prevailing notion has long been that vessels themselves are composed of largely similar ECs. Instead, data from our labs challenge this view by showing that vessels are built of highly diverse ECs displaying different behavioral properties, a feature we term intravessel EC behavioral mosaicism. While these findings are promising, there is still much to learn about the range of behavioral variability among ECs within vessels and how this intricate mosaic of behaviors is orchestrated to optimize vascular function. Building on our past achievements, we now aim towards novel directions- to push forward a fresh conception of vessels, as mosaic composites of specialized ECs. Here, we will integrate our synergistic expertise in live imaging, sophisticated genetic approaches, and spatial omics to map EC behaviors in zebrafish and mice. In addition, we will harness oncogenic mutations causing vascular malformations in humans to investigate how they alter the behavioral map. Finally, we will decode mechanisms of vessel tolerance and co-optation in response to stochastic expression of mutations to understand how vessels cope with EC mosaic behaviors. The important and unique aspects of our approach are the focus on in vivo dynamics and the cross-animal and organ comparisons, which will provide much needed knowledge on vessel architecture and function, making substantial advances at the frontier of vascular biology. Overall, we envision that shifting the paradigm of vessel heterogeneity to behavioral mosaicism will provide a better understanding of vascular-related pathologies and will lay the foundation for improving vascular therapies by targeting specific EC subsets. Moreover, we expect to offer means to understand other diseases involving mosaic responses, including cancer.