The class mammalia is composed of approximately 4800 extant species. This class is divided into three subclasses, the prototheria (monotremes), metatheria (marsupials), and eutheria. Surprisingly, there is relatively little knowledge about germ layer and axis formation in mammalian species. Most knowledge about these embryonic processes has been obtained from one species, the mouse, Mus musculus. Here we discuss major variations in germ layer and axis formation among mammals. We suggest that more studies of embryonic development in diverse mammalian species are required for an understanding of germ layer and axis formation to provide insights into human biology and disease.