The localized structural abnormalities that arise during vasculogenesis, angiogenesis and lymphangiogenesis, the developmental processes which give rise to the adult vasculature, are collectively termed vascular anomalies. The last 2 years have seen an explosion of studies that underscore paradominant inheritance, the combination of inherited changes with somatic second-hits to the same genes, as underlying rare familial forms. Moreover, local, somatic genetic defects that cause some of the common sporadic forms of these malformations have been unraveled. This highlights the importance of assessing for tissue-based genetic changes, especially acquired genetic changes, as possible pathophysiological causes, which have been largely overlooked except in the area of cancer research. Large-scale somatic screens will therefore be essential in uncovering the nature and prevalence of such changes, and their downstream effects. The identification of disease genes combined with exhaustive, precise clinical delineations of the entire spectra of associated phenotypes guides better management and genetic counseling. Such a synthesis of information on functional and phenotypic effects will enable us to make and use animal models to test less invasive, targeted, perhaps locally administered, biological therapies.