Transgender people have a gender that is not in agreement with their birth sex. Previous barriers, including lack of provider knowledge, have created significant healthcare disparities for this population. Recent societal changes are increasing the numbers of transgender people seen by primary care practitioners. Ten key principles are provided to help primary care practitioners create more welcoming environments and provide quality care to transgender patients. Overall, all members of the healthcare team (primary and specialty) need to become aware of the transition process and maintain communication regarding risks, benefits, and goals. Transwomen (aka male to female) can be treated with estrogens, antiandrogens, or a combination. Benefits include change in fat distribution, skin softening, and breast development. Significant risks for thrombosis from estrogens have been linked to genetic mutations, smoking, prolonged inactivity, and hormone formulation. Oral administration may provide increased risk over peripheral administration. Transmen (aka female to male) can be treated with peripheral testosterone preparations. Benefits include deepening of voice and development of facial and body hair with variable changes in muscle mass. Risks from testosterone appear to be less common than from estrogen. Laboratory monitoring can guide treatment decisions and provide early detection of some complications. Monitoring of “existing” anatomy (either hormonally or surgically created or removed) is an important component of healthcare for transgender patients. Primary care providers also should be aware of resources in their community and online, which can help patients optimize their transition.