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The nervous system is operated by complex and dynamic cellular networks that generate functional outputs in response to external stimuli or physiological state changes. Neurotransmission, the major communication process between neurons, is fundamental for a broad range of neural functions. Due to the anatomical, cellular, and molecular complexity of the nervous system, decoding neurotransmission requires tools/methods that enable control over signaling mediators with high spatial, temporal, and biological precision. I will introduce two strategies, optogenetics and photopharmacology, that exhibit unique strengths for tackling this outstanding challenge. To control neurotransmitter release from genetically-defined neurons, my laboratory engineers light-activated potassium channels for optogenetic silencing of presynaptic activities. To control neurotransmission without genetic manipulation, we develop photoswitchable ligands that can reversibly modulate neurotransmitter receptors through illumination. In the future, we will integrate the concepts of these strategies to achieve optical control of bona fide neurotransmission with cellular and subcellular specificity. Through these efforts, we hope to provide potent and specialized tools to decode neurotransmission in health and diseases, uncovering unexplored opportunities for biomedical discoveries.