SYNOPSIS. Several phases of animal evolution have undergone radical change in developmental mechanisms. I refer to these as major transitions in animal evolution. The six most important transitions in the lineage leading to humans are proposed to be: the origin of multicellularity, the origin of two-germ layers and radial symmetry, the origin of three-germ layers and bilateral symmetry, dorsoventral axis inversion, the origin of vertebrates, the origin of gnathostomes. Here I discuss the genetic changes that may have underlain these transitions. The last two transitions were accompanied by, and possibly facilitated by, large increases in gene number. This probably occurred by tetraploidy, with some of the duplicate genes being subsequently lost. The origin of three germ-layers, bilateral symmetry and a through gut also probably involved gene duplication; in this case, duplication of an ancestral ProtoHox gene cluster to yield two paralogous homeobox gene clusters, Hox and ParaHox, with roles in patterning different germ layers along the anteroposterior body axis. This event may provide a partial genetic explanation for the Cambrian explosion.