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Transsexual presentations in primary care stress mainstream health care physical resources, institutional organization, and the cultural flexibility of providers and interdisciplinary staff. This article describes the ethical landscape, examines gender identity culture, and considers gender reassignment physiology. Nurse practitioners are challenged to advocate for this population.Sources for the discussion derive from published institutional guidelines, institutional and civic policies, web-based information in the public domain, and professional journal articles.Advocacy for cultural sensitivity, institutional policy change,and professional integrity will determine healthcare quality for this population. Advocacy for cultural awareness and institutional change has begun in larger institutions and metropolitan areas, but is necessary across primary care settings.Caring for transsexuals requires knowledge of anatomical reassignments, hormonal therapy effects, and cultural sensitivities particular to the gender identity community. Healthcare screening and physical exam modifications for these presentations require forethought and appropriate adjustments.