Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is intended to evaluate the short-term (12 weeks) and longer-term (36 weeks) effectiveness of four treatments for adolescents with DSM-IV major depressive disorder: clinical management with fluoxetine (FLX), cognitive-behavioral therapy (CBT), FLX and CBT combined (COMB), and clinical management with placebo (PBO). We previously reported that COMB and FLX were more effective in reducing depression than CBT or PBO after 12 weeks of acute treatment. In this special section of the Journal, separate articles extend these findings to the impact of TADS treatments on remission, speed of response, function and quality of life, predictors of outcome, and safety during the first 12 weeks of treatment. To set the stage for the special section, we briefly review the rationale, design, and methods of the TADS; describe the TADS sample to which the TADS findings generalize; using all of the currently available data, summarize the intent-to-treat outcomes across multiple endpoints at 12 weeks; and consider the public health value of the TADS findings in the context of design decisions and methodological limitations of the TADS, including some that may have advantaged the combined treatment condition. Reflecting the ordering of effect sizes at week 12--COMB (0.98) greater than FLX (0.68) greater than CBT (-0.03)--combined treatment proved superior to PBO on 15 of 16 endpoints, to CBT on 14 of 16 endpoints, and to FLX on 8 of 16 endpoints, whereas FLX was superior to CBT on 8 of 14 and to PBO on 7 of 16 measures. CBT did not differ from PBO on any measure. Despite the fact that suicidality improved markedly across all of the treatment conditions, suicidal events were twice as common in patients treated with FLX alone than with COMB or CBT alone, perhaps indicating that CBT protects against suicidal events. Thus, combined treatment appears to accelerate recovery relative to CBT and, for some outcomes, FLX alone, while minimizing the risk of suicidality relative to FLX alone. Taking benefit and risk into account, we conclude that the combination of FLX and CBT appears superior to either monotherapy as a treatment for moderate to severe major depressive disorder in adolescents. (Contains 1 table.)