Human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) significantly burden youth aged 13-24 years in the United States. Directly engaging youth in sexual health research is a public health priority and urgently needed to develop targeted, youth-friendly, and culturally relevant HIV/STI prevention interventions. Controversies arise, however, regarding informed assent and consent, parental permission or consent, and the definition of "child"/"minor" as it relates to medical, legal and ethical issues. In this paper, we describe challenges in the human subjects review processes that were undertaken before beginning an HIV/STI prevention research project with sexually active youth in an urban setting. These findings provide important contextual information to facilitate youth sexual health research and care, and Institutional Review Board approval processes with fewer delays.