Gender transition is undertaken to improve the well-being of people suffering from gender dysphoria. However, some have argued that the evidence supporting medical interventions for gender transition (e.g., hormonal therapies and surgery) is weak and inconclusive, and an increasing number of people have come forward recently to share their experiences of transition regret and detransition. In this essay, I discuss emerging clinical and research issues related to transition regret and detransition with the aim of arming clinicians with the latest information so they can support patients navigating the challenges of regret and detransition. I begin by describing recent changes in the epidemiology of gender dysphoria, conceptualization of transgender identification, and models of care. I then discuss the potential impact of these changes on regret and detransition; the prevalence of desistance, regret, and detransition; reasons for detransition; and medical and mental healthcare needs of detransitioners. Although recent data have shed light on a complex range of experiences that lead people to detransition, research remains very much in its infancy. Little is known about the medical and mental healthcare needs of these patients, and there is currently no guidance on best practices for clinicians involved in their care. Moreover, the term detransition can hold a wide array of possible meanings for transgender-identifying people, detransitioners, and researchers, leading to inconsistences in its usage. Moving forward, minimizing harm will require conducting robust research, challenging fundamental assumptions, scrutinizing of practice patterns, and embracing debate.