Each year, 3 million US teenagers are infected with a sexually transmitted infection (STI). Given the variability present in female adolescents in terms of maturation (biological, cognitive, and psychosexual), sexual knowledge and experiences, interpersonal skills, and sociocultural contexts, programs targeted at this group must use a developmental perspective. This paper reviews the bidirectional impact of the relationships between these developmental factors. Sexual behavior in adolescence is determined by the individual's assessment of risk and regulated by consequences that are subjectively interpreted. Adolescent girls vary significantly in the extent to which they perceive they have control over STI preventive behaviors. A belief in control over one's fate is both developmental in nature and culturally specific. Adolescent girls who contract an STI are likely to react with emotion-focused coping strategies, including wishful thinking. Interventions aimed at this group must be multidisciplinary and address biomedical, behavioral/psychological, and cultural interventions.