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Neurochemicals have a large impact on brain states and animal behavior but are notoriously hard to detect accurately in the living brain. Recently developed genetically encoded sensors obtained from engineering a circularly permuted green fluorescent protein into G-protein coupled receptors (GPCR) provided a vital boost to neuroscience, by innovating the way we monitor neural communication. These new probes are becoming widely successful due to their flexible combination with state of the art optogenetic tools and in vivo imaging techniques, mainly fiber photometry and 2-photon microscopy, to dissect dynamic changes in brain chemicals with unprecedented spatial and temporal resolution. Here, we highlight current approaches and challenges as well as novel insights in the process of GPCR sensor development, and discuss possible future directions of the field.