This article is a literature review of high-risk behaviors, including sexual activity, in adolescents with chronic illness. Three different models describing biopsychosocial constructs for risky behaviors are discussed. Regarding specific behaviors, findings from the literature include a substantial prevalence of sexual activity, but low level of knowledge and low prevalence of contraceptive use, in youth with chronic illness. Regarding substance use, alcohol was the most commonly used substance regardless of medical condition. Overall, substance use, as well as delinquent behavior, was lower among youth with chronic illness when compared to that in comparison groups. Results were mixed regarding the prevalence and determinants of unhealthy eating habits in these populations. Although high-risk behaviors in teenagers with chronic illness may be a normal part of development, awareness of their prevalence, along with early identification and counseling are important in order to anticipate adverse effects on their medical conditions.