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With nominations from leading scientists studying cell signaling, the STKE editors compile a list of the year's most important advances. Signaling breakthroughs included molecules and processes both outside cells and inside cells, from channels in the membrane to chromatin in the nucleus. The nominated research ranged from structural and functional revelations to approaches for the global analysis of signaling pathways. Receptors were highlighted with unexpected proteins functioning as receptors, as well as surprising functions for known receptors. This year also brought new insights into the impact of cell signaling on human physiology and disease.