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With input from the members of the Board of Reviewing Editors and editorial staff, Science Signaling puts the spotlight on the hottest signaling research of 2012. The connection between signaling and metabolism continues to be an important area. Signaling breakthroughs in cancer, immunology, developmental biology, neuroscience, and microbiology all made the list. Structural and molecular insights into signaling proteins and networks are also beginning to not only yield potential therapeutic targets but also lead to successful efforts between synthetic biologists and clinicians in the treatment of cancer.