--- - |2+ Background Within the past decade, health care service and research priorities have shifted from evidence‐based medicine to personalized medicine. In mental health care, a similar shift to personalized intervention may boost the effectiveness and clinical utility of empirically supported therapies (ESTs). The emerging science of personalized intervention will need to encompass evidence‐based methods for determining which problems to target and in which order, selecting treatments and deciding whether and how to combine them, and informing ongoing clinical decision‐making through monitoring of treatment response throughout episodes of care. We review efforts to develop these methods, drawing primarily from psychotherapy research with youths. Then we propose strategies for building a science of personalized intervention in youth mental health. Findings The growing evidence base for personalizing interventions includes research on therapies adapted for specific subgroups; treatments targeting youths’ environments; modular therapies; sequential, multiple assignment, randomized trials; measurement feedback systems; meta‐analyses comparing treatments for specific patient characteristics; data‐mining decision trees; and individualized metrics. Conclusion The science of personalized intervention presents questions that can be addressed in several ways. First, to evaluate and organize personalized interventions, we propose modifying the system used to evaluate and organize ESTs. Second, to help personalizing research keep pace with practice needs, we propose exploiting existing randomized trial data to inform personalizing approaches, prioritizing the personalizing approaches likely to have the greatest impact, conducting more idiographic research, and studying tailoring strategies in usual care. Third, to encourage clinicians’ use of personalized intervention research to inform their practice, we propose expanding outlets for research summaries and case studies, developing heuristic frameworks that incorporate personalizing approaches into practice, and integrating personalizing approaches into service delivery systems. Finally, to build a richer understanding of how and why treatments work for particular individuals, we propose accelerating research to identify mediators within and across RCTs, to isolate mechanisms of change, and to inform the shift from diagnoses to psychopathological processes. This ambitious agenda for personalized intervention science, although challenging, could markedly alter the nature of mental health care and the benefit provided to youths and families. - Journal of Child Psychology and Psychiatry, Page 216-236, October 2018.