This is a peer-reviewed chapter in an open access book, Human Microbiome. This chapter is a highly technical synopsis of the relationship between the human gut microbiome and the brain, also known as the gut-microbiome-brain axis. In both medicine and nutrition, this is an expanding field of inquiry. Chemical molecules involved in this “dialogue” are examined. The author provides a brief overview of animal experiments and concludes with a discussion of the significance of the microbiome on human mental health. The chapter is clear, timely and relevant. It is a technical reading that is best suited to nurses, physicians, nutritionists, and other allied health professionals at both the undergraduate and graduate level. This chapter is also of special interest to researchers.