AIMS: We explored the in vivo effects of knockdown of caldesmon on vascular development in zebrafish. METHODS AND RESULTS: We investigated the effects of caldesmon knockdown on the vascular development in a zebrafish model with special attention for the trunk and head vessels including the aortic arches. We examined the developing fish at various time points. The vascular abnormalities observed in the caldesmon morphants (CaD-MOs) were morphologically and functionally characterized in detail in fixed and living embryos. The knockdown of caldesmon caused serious defects in vasculogenesis and angiogenesis in zebrafish morphants and the vascular integrity and blood circulation were concomitantly impaired. CONCLUSION: The data provide the first functional assessment of the role of caldesmon in vascular development in vivo, indicating that this molecule plays a crucial role in vasculogenesis and angiogenesis in vivo. Interfering with caldesmon opens new therapeutic avenues for anti-angiogenesis in cancer and ischemic cardiovascular disease.