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. 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). 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 (>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. 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.