As the number of transgender individuals continues to rise, there is an urgent need to understand the nature of gender and the evidence supporting gender-affirming care. This article proposes the hypothesis that one’s gender is a perception, influenced by biological and social factors. Early-onset gender incongruence seems to be influenced but not wholly determined by the prenatal hormonal environment, while late-onset gender incongruence is associated with comorbidities, suggesting that one’s sense of gender can be impacted by a variety of psychological and social conditions that affect the mind-body connection. Puberty blockers have been used on children to buy time for them to decide whether to continue with their transition. However, most gender dysphoria desists at puberty, but this is prevented by puberty blockers. Moreover, puberty blockers have negative psychological and physiological consequences, and studies of puberty blockers and cross-sex hormones have not shown long-term improvements in mental health outcomes. Thus, while some gender incongruence does not resolve upon puberty and may be best treated by transitioning, the preponderance of evidence does not support a medicalized gender-affirming approach for children and adolescents.