Increasing numbers of transgender and nonbinary youth are now accessing gender-affirming medical interventions, which have been demonstrated to improve health and well-being. This Perspective addresses how the needs of transgender and nonbinary youth, up to age 18, can be addressed through individualized gender-embodiment care. We first review standard medical therapies, including gonadotropin-releasing hormone analogues, 17β-oestradiol, testosterone, steroidal antiandrogens and progestins, followed by presenting novel approaches to individualizing gender healthcare for transgender and nonbinary youth, consisting of selective oestrogen receptor modulators, 5α-reductase inhibitors, aromatase inhibitors and non-steroidal antiandrogens. Ethical guidance for off-label prescribing is provided, grounded in the principles of evidence, benefit, safety, respect, care, communication, transparency, equity and innovation. These ethical principles are applied in three clinical scenarios in which off-label therapies are considered. We conclude that standard medical therapies are ethically justified and that novel therapies can be ethically acceptable when carefully considered in the context of an individual youth's care plan and taking into account the available theoretical, clinical and research evidence as well as the potential benefits and potential risks. In keeping with the principle of innovation, we encourage clinicians and researchers to share evidence of medical innovations that support the gender health of transgender and nonbinary youth.