Maintenance of apoptosis protection and migratory capacity are absolutely required for proper endothelial function. Several pathways are described, which are necessary for these processes including activation of the protein kinase B (Akt) and the endothelial nitric oxide synthase (eNOS). Recently, we identified a new player, the transcription factor sister-of-mammalian grainyhead (SOM)/Grainyhead-like 3, which demonstrated anti-apoptotic and pro-migratory properties in endothelial cells (EC). In humans, three isoforms of SOM are expressed, two of which, SOM1 and SOM3, are derived from an alternatively spliced transcript. SOM3 lacks exon 2, described to contain the putative transactivation domain, and thus, has been suggested to be a repressor. SOM1 and SOM3 are co-expressed in numerous tissues, however, their exact cellular functions have not been investigated so far. Here we demonstrate that SOM1 and SOM3 are expressed in primary human EC. In contrast to published data, which were based on a yeast two hybrid analysis with isolated domains, we could show that both full length proteins are transcriptional activators. Moreover, they have opposing functions in EC and in a whole animal model. Overexpression of SOM1 inhibited apoptosis and induced migration of EC. The latter effect could be due to the observed activation of eNOS and its upstream regulator Akt. On the contrary, SOM3 has no effect on apoptosis and significantly inhibits migration and eNOS activation. To assess the in vivo relevance of the opposing effects of SOM1 and SOM3, we made use of zebrafish as a whole animal model. SOM3, but not SOM1, induced severe malformations in embryos and reduced the number of normally developed embryos significantly. Microarray analyses showed that SOM1 and SOM3 have some overlapping, but an even larger number of distinct target genes. Our data suggest that the opposing effects of the two SOM isoforms are mediated by transcriptome alterations and that a switch in isoform expression could change the cellular fate with dramatic consequences for a whole organism.