Background: Migration of the native populations from reservations to the urban areas has resulted in mixed ethnicities of American Indian/Alaskan Native (AIAN) children. Minority youth require special attention and services in urban schools as they disproportionately experience poverty, low educational attainment, unemployment, and single-parent status. Methods: We used 2005 and 2007 Youth Risk Behavior Survey data to examine alcohol/drug use patterns and their association with sexual risk taking among AIAN only (single-racial) and biracial youth in combination with White, African American, or Hispanic ethnicities (N = 1178). Results: Overall, one half of the students were sexually active, with significantly higher rates among males; AIAN-Black students initiated sex earlier than the other groups. Condom nonuse is higher among AIAN-Whites (greater than 50%) compared to one third of AIAN-Hispanics and one fourth of AIAN-Blacks. Nearly 10% of all students, except AIAN-Blacks, reported lifetime use of heroin/meth. Sexual behavior was significantly associated with episodic drinking. Students with Hispanic background have twice the odds of being sexually active compared to AIANs. Conclusions: Our findings underscore growing health care needs and targeted prevention initiatives for mixed racial underserved native youth. Urban school settings have potential to deliver services and offer alcohol/drug prevention programs to address the needs of mixed racial native urban youth. Using the School Based Health Clinic model has been successful; we need to reform prevention approaches to accommodate needs of multiracial urban native youth. (Contains 4 tables.)