In Xenopus embryos, body patterning and cell specification are initiated by transcription factors, which are themselves transcribed during oogenesis, and their mRNAs are stored for use after fertilization. We have previously shown that the T-box transcription factor VegT is both necessary and sufficient to initiate transcription of all endoderm, and most mesoderm genes. In the absence of maternal VegT, no mesodermal organs (including the heart) or endodermal organs form. A second maternal transcription factor XTcf3 acts as a global repressor of transcription of dorsal genes, whose repression is inactivated on the dorsal side by a maternally encoded Wnt signaling pathway. In the absence of beta-catenin, no mesodermal or endodermal organs form. We show here that the maternally encoded transcription factor CREB is also essential for development. It is required for the initiation of expression of several mesodermal genes, including Xbra, Xcad2, and -3 and also regulates the cardiogenic gene Nkx 2-5. We show that maternal CREB-depleted embryos develop gastrulation defects that are rescued by the reintroduction of activated CREB mRNA. We conclude that maternal CREB must be added to the list of essential maternal transcription factors regulating cell specification in the early embryo.