This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress. This Phased Innovation Awards Cooperative Agreement Funding Opportunity Announcement (FOA) solicits applications to support a collaborative research infrastructure involving an interdisciplinary team of basic and clinical scientists to develop the foundation for an experimental medicine approach to behavior change. Research supported by this FOA is meant to support activities focused on behavior change targets in the domain of stress reactivity and stress resilience through four main target validation steps: 1. Identify a set of putative targets within the stress reactivity and stress resilience domain that are implicated in medical regimen adherence and at least one other health behavior;; 2. Leverage existing or develop new experimental or intervention approaches to engage identified targets; 3. Identify or develop appropriate assays (measures) to permit verification of target engagement; 4. Test the degree to which engaging identified targets produces a desired change in medical regimen adherence and at least one other health behavior. While testing target engagement in specific clinical samples is permitted, the targets identified and the behavior change outcomes measured should be selected based on their hypothesized relevance to at least two clinical endpoints or disease conditions. Funds from the NIH will be made available through the UH2/UH3 Phased Innovation Awards Cooperative Agreement mechanism.The initial UH2 phase will support steps 1-3 above. UH2 projects that have met their objectives and agreed upon milestones will be administratively considered by NIH and prioritized for transition to the UH3 validation phase to complete step 4 above. Projects proposed in response to this FOA will require multidisciplinary efforts and therefore all applicant teams must include expertise in basic and clinical science. Investigators responding to this FOA must address both UH2 and UH3 phases. The output of these UH2/UH3 Target Validation Projects, to be facilitated by a Resource and Coordinating Center (RCC) funded under a companion RFA-RM-14-017, will be a toolkit of validated and documented assays of specific targets in the domain of stress reactivity and stress resilience, and experimental manipulations/interventions that engage those targets. Please refer to the Science of Behavior Change SOBC website regularly for updates, frequently asked questions (FAQs), and other announcements related to this FOA and the companion FOAs. SOBC Website: http://commonfund.nih.gov/behaviorchange/ FAQs: http://commonfund.nih.gov/behaviorchange/faq