Progesterone is an endogenous steroid hormone with an important role for the physiology of the female reproductive system and the mammary gland. It has additional significant actions in other tissues, such as the cardiovascular system, the central nervous system, and bones. The present article explores potential clinical implications from the addition of bioidentical progesterone to gender-affirming treatment of trans women. For this purpose, it provides an overview of the physiological action of progesterone in target tissues and speculates on possible benefits for gender transitioning. Progesterone is expected to exert moderate anti-androgen action through suppression of the hypothalamic-pituitary-gonadal axis and inhibition of the conversion of testosterone to dihydrotestosterone. It may also contribute to breast maturation. In the long-term, progesterone could prevent bone loss and protect cardiovascular health. The potential benefits are mainly inferred by extrapolating evidence from biological actions in cisgender women and medical assumptions and hence, clinicians need to be cautious when applying these data into practice. Further research is needed to ascertain the efficacy and safety of progesterone in current hormonal regimens.