The life sciences rest on a new footing in which symbiotic microbes are recognized as fundamental to nearly every aspect of host form, function, and fitness. As a result, today's challenge is to unite Mendelian genetics and symbiosis in our general models and experiments of animal and plant evolution. In this talk, I will discuss how we are elucidating the varied ways in which the microbiome interacts with the nuclear genome to drive animal evolution, including what Darwin referred to as the definitive “mystery of mysteries”.