We developed a new class of genetically-encoded indicators of neuronal function with greatly improved properties. GCaMP6 indicators cross important performance thresholds. They have higher sensitivity than commonly used synthetic calcium dyes (e.g., OGB1) and detect individual action potentials with high reliability at reasonable microscope magnifications. These indicators can be used to image large groups of neurons as well as tiny synaptic compartments over multiple imaging sessions separated by months. It is likely that these sensors will find widespread applications for diverse problems in brain research and calcium signaling. Future engineering efforts could focus on red fluorescent calcium indicator proteins48,49, which promise imaging considerably deeper in scattering tissue50.