Genetic variation in holobionts (host and microbiome), occurring in both host and microbiome genomes, can be observed from two perspectives: observable variations and processes that bring about the variation. Observable includes the enormous genetic diversity of prokaryotes, which gave rise to eukaryotes. Holobionts then evolved a rich microbiome with a stable core containing essential genes, less so common taxa and a more diverse non-core, enabling considerable genetic variation. Thus, the human gut microbiome, for example, contains 1000 times more unique genes than are present in the human genome. Microbial-driven genetic variation processes in holobionts include: (1) acquisition of novel microbes from the environment, (2) amplification/reduction of certain microbes in the microbiome, (3) horizontal gene transfer between microbes and between microbes and host and (4) mutation, which plays a role in optimizing interactions between microbiota and between microbiota and host. We suggest that invertebrates and plants, where microbes can live intracellularly, have a greater chance of genetic exchange between microbiota and host, a greater chance of vertical transmission and a greater effect of microbiome on evolution than vertebrates. However, even in vertebrates the microbiome can aid in environmental fluctuations by amplification/reduction and by acquisition of novel microorganisms.