Most preclinical and clinical, animal, and human research has been biased with respect to sex and even more so with respect to gender. In fact, little is known about the impact of sex and even less about the influence of gender on overall metabolic processes. The National Institutes of Health has recognized this gap in scientific knowledge and now mandates that studies be conducted in both sexes and to include gender as variables influencing physiological processes such as metabolism. It is therefore critical to understand and appreciate how to incorporate sex and gender in preclinical and clinical research in order to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. In this chapter, we define sex and gender and discuss when sex and gender are not aligned, such as that which occurs in transgender individuals, and how this impacts metabolic processes. We discuss the importance of understanding the influence and interactions between sex hormones and sex chromosomes rather than focusing on their relative contributions to metabolism in isolation. This knowledge will optimize therapies specific for individuals which need to encompass sex and gender.